Megan M. Wickens
Debra A. Bangasser
Lisa A. Briand- 1Department of Psychology and Neuroscience Program, Temple University, Philadelphia, PA, United States
- 2Neuroscience Program, Temple University, Philadelphia, PA, United States
Alterations in glutamate, the primary excitatory neurotransmitter in the brain, are implicated in several psychiatric diseases. Many of these psychiatric diseases display epidemiological sex differences, with either males or females exhibiting different symptoms or disease prevalence. However, little work has considered the interaction of disrupted glutamatergic transmission and sex on disease states. This review describes the clinical and preclinical evidence for these sex differences with a focus on two conditions that are more prevalent in women: Alzheimer's disease and major depressive disorder, and three conditions that are more prevalent in men: schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. These studies reveal sex differences at multiple levels in the glutamate system including metabolic markers, receptor levels, genetic interactions, and therapeutic responses to glutamatergic drugs. Our survey of the current literature revealed a considerable need for more evaluations of sex differences in future studies examining the role of the glutamate system in psychiatric disease. Gaining a more thorough understanding of how sex differences in the glutamate system contribute to psychiatric disease could provide novel avenues for the development of sex-specific pharmacotherapies.
Introduction
Accumulating data indicate that disruptions in glutamate neurotransmission are a common underlying pathology in multiple psychiatric diseases including Alzheimer's disease (AD), major depressive disorder (MDD), schizophrenia (SCZ), autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD) (Magri et al., 2008; Counts et al., 2011; Shimmura et al., 2011; Sokolow et al., 2012; Gray et al., 2015). Furthermore, these diseases all exhibit a sex bias, with increased prevalence of ASD and SCZ in men and increased prevalence of MD and AD in women (Fombonne, 2005; Noble, 2005; Markham, 2012; Mielke et al., 2014). Although little work has been done to elucidate baseline sex differences in the glutamate system, it is clear from work in these disease populations that sex differences must be considered. To promote a better understanding of these sex biases in disease along with sex differences in treatment response, we must first gain a better understanding of sex differences in the glutamate system. To date, very little work has been done to elucidate these differences. This review will focus on the sex differences in the glutamate system that have been revealed in clinical populations and preclinical studies of glutamatergic sex differences, highlighting how much more work is needed to obtain a clear picture of how sex differences in the glutamate system contribute to disease.
The Glutamate System
Glutamate is the primary excitatory neurotransmitter in the brain and it is essential for normal brain development and plasticity. Glutamate receptors come in two types, ionotropic ligand-gated ion channels and metabotropic, G-protein coupled receptors. These receptor subtypes can be even further subdivided. Currently there are 8 identified metabotropic glutamate receptors: mGluR1-8, and 3 identified ionotropic glutamate receptor subtypes: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, N-methyl-D-aspartate (NMDA) receptors, and kainate receptors. These receptor subtypes can be further divided based upon their subunit composition. AMPA receptors may be calcium-permeable or calcium-impermeable, depending on the absence or presence of the GluA2 subunit, respectively (Hanley, 2014). NMDA receptors are composed of two GluN1 and two GluN2 (or rarely GluN3 subunits). The four subtypes of GluN2 subunits (GluN2A-2D) confer functional diversity with each GluN2 subunit exhibiting unique biophysical, pharmacological and signaling properties (Paoletti et al., 2013; Sanz-Clemente et al., 2013; Wyllie et al., 2013; Ferreira et al., 2017). After being cleared from the synapse by excitatory amino acid transporters (EEATs), glutamate is converted to glutamine. As the levels of both glutamate and glutamine can be measured using proton magnetic resonance spectroscopy (MRS) in humans, many studies have examined these amino acids as potential biomarkers for psychiatric disease (Shimmura et al., 2011; Chiu et al., 2018; Sheikh-Bahaei et al., 2018).
Sex Differences in Glutamate Systems
Baseline Differences
The little work that has been done in humans to elucidate sex differences in the glutamate system has led to somewhat mixed results. MRS studies have demonstrated a slight increase in glutamate concentration within the parietal gray matter of men compared to women, while no differences were detected in the frontal gray or white matter or the basal ganglia (Sailasuta et al., 2008). However, when looking more carefully at specific brain regions, women seem to exhibit higher levels of glutamate compared to men. Specifically, women exhibit increased glutamate levels in the striatum and cerebellum compared to men (Zahr et al., 2013). There also appears to be increases in glutamate within the sensorimotor cortex and anterior cingulate cortex (ACC) of women (Grachev and Apkarian, 2000). Along with these studies examining glutamate within the brain, studies have also shown sex differences in serum glutamate concentration (Stover and Kempski, 2005; Teichberg et al., 2009). In contrast to the majority of studies examining glutamate in the brain, studies in blood have revealed higher glutamate concentrations in men compared to women (Zlotnik et al., 2011). As glutamate is present in many tissues in the body, these differences in serum glutamate may not reflect changes within the central nervous system (Shulman et al., 2006).
Sex differences in the glutamate system are more readily examined in rodent models. Several brain regions in rodents show sex differences in glutamate concentrations, including higher glutamate in the lateral hypothalamus and habenula of males and higher glutamate in the medial preoptic area of females (Frankfurt et al., 1984). Along with these overall sex differences in glutamate levels there are also changes in glutamate concentration across the estrous cycle (Frankfurt et al., 1984). These changes are brain region specific, with higher levels observed in the lateral septum during proestrus—the phase of the cycle where ovarian hormones are highest—compared to estrus; in the medial septum and diagonal band of Broca during proestrus compared to diestrus; and lower in the anterior hypothalamic area during proestrus compared to diestrus (Frankfurt et al., 1984).
Sex differences are also observed in synaptic glutamate signaling. Under basal conditions, female rats show larger hippocampal AMPR receptor synaptic responses, possibly due to enhanced phosphorylation of the GluA2 subunit (Monfort et al., 2015). However, this enhanced glutamate signaling may occlude further plasticity. Female rats show a reduction in the magnitude of tetanus-induced long-term potentiation (LTP) compared to male rats and this reduction is associated with a decrease in tetanus-induced phosphorylation of GluA1 (Monfort et al., 2015). As the phosphorylation of GluA1 AMPA subunits is involved in the insertion of GluA1-containing AMPR receptors into the synapse, this could reflect a mechanism for this diminished synaptic plasticity (Man et al., 2007). Along with these alterations in AMPA receptor signaling, sex differences also exist in NMDA receptor signaling. For example, NMDA antagonism increases prefrontal dopamine in male rats but decreases levels in females (Locklear et al., 2016). This may reflect a leftward shift in the dose response curve since females seem to be more sensitive to NMDA receptor manipulations. Female rats are more sensitive to excitotoxic damage following administration of an NMDA receptor antagonist, MK-801 (Wozniak et al., 1998) and exhibit a greater behavioral response to ketamine, an NDMA receptor antagonist (McDougall et al., 2017). This increase in NMDA sensitivity may be the result of increased receptor expression as female rats exhibit higher levels of both NR1 and NR2B NMDA subunits (Wang et al., 2015). Along with these changes in ionotropic glutamate signaling, there also appear to be basal sex differences in the metabotropic glutamate receptor system, with female rats exhibiting higher levels of mGluR2/3 and mGluR5 within the hippocampus along with increased mGluR5 in the prefrontal cortex (Wang et al., 2015). Steroid hormones may influence this overall increase in glutamatergic transmission. The neurosteroid, 17β-estradiol (E2) is known to potentiate excitatory transmission by increasing the probability of glutamate release in females (Smejkalova and Woolley, 2010).
Changes Across the Lifespan
While relatively subtle sex differences in glutamate exist in healthy younger individuals, more dramatic sex differences seem to emerge with age. When examining glutamate levels in the brain across the lifespan, men exhibit a clear decline in glutamate from age 21 to age 70 within the basal ganglia and the parietal gray matter that is not present in women (Sailasuta et al., 2008). However, in the ACC, women show a more pronounced age-related decline (between ages 19 and 56) in glutamate levels compared to men (Hädel et al., 2013). Healthy men have been shown to have higher levels of glutamine (Gln) in the ACC, compared to healthy women (Tayoshi et al., 2009). In serum, women exhibit an increase in glutamate concentration as they age (from age 20 to 80), whereas men do not (Kouchiwa et al., 2012). Along with these age-related changes in glutamate levels, there appear to be changes in glutamate receptors as well. Over the course of aging (age 25 vs. age 70), men exhibit an increase in the distribution of mGluR1 in the cerebellum, parietal cortex, putamen, amygdala, and hippocampus (Sakata et al., 2017). Women do not show these aging-related differences in mGluR1 distribution (Sakata et al., 2017). Postmortem tissue analysis has demonstrated that glutamate related gene expression, including genes that code for glutamate receptors and trafficking proteins, decrease over the first 50 years of life within the prefrontal cortex (Choi et al., 2009). However, no studies have yet been adequately powered to detect normal sex differences in these effects nor have more advanced ages been examined. Nevertheless, studies on aging and disease provide us with some insight into potential differences.
Similar to the changes in the glutamate system that occur across the lifespan in humans, rodents also exhibit developmental changes in glutamate. Glutamate concentrations rise over the first 3 months of life in both male and female mice (Kulak et al., 2010). These changes in the glutamate system do not stop when animals reach adulthood. Glutamate concentrations decrease over the course of aging in the hippocampus, cortex, and striatum (Duarte et al., 2014). Although there were no sex differences in the total glutamate concentrations, the authors report a significant interaction between age and brain region in the ratio of glutamine/glutamate, which may reflect differences in glutamatergic transmission between neurons and glial cells (Duarte et al., 2014). Decreased levels of GluA1, GluN2A, and GluN2B glutamate receptor subunit levels over the course of aging (6 mo vs. 24 mos) have been correlated with poorer cognitive performance in male rats, but these studies have not been done in females (Ménard et al., 2015).
Taken together, although much more work is needed to fully understand sex differences in the glutamate system, there appears to be an overall increase in glutamate transmission in females. This increase may be subtle in young adulthood but during aging glutamate transmission decreases in males and the sex difference is amplified. These alterations in glutamate transmission at different ages could contribute to sex differences in incidence, symptomology, and treatment response for many psychiatric diseases. However, much more work is needed to examine differences within the glutamate system in different brain regions in males and females and determine whether there is in fact an overall increase in glutamate tone in females or if the differences are more subtle.
Sex Differences in Glutamate Systems in Disease
Alzheimer's Disease
Alzheimer's disease (AD) is the leading cause of dementia and it is more likely to affect women than men, with nearly two-thirds of AD cases being women (Mielke et al., 2014). AD is characterized by accumulation of amyloid beta (Aβ) oligomers that are able to block glutamate uptake, leading to increased glutamate levels (Mattson et al., 1992; Domingues et al., 2007). This increased glutamate can lead to excitotoxicity and neurodegeneration. Dampening glutamate transmission can be helpful in the treatment of AD, as the non-competitive NMDA receptor antagonist memantine shows efficacy in the management of moderate-to-severe AD (Reisberg et al., 2003; Winblad et al., 2007). This increase in glutamate levels could more severely impact women with AD as they exhibit lower levels of GluA2-containing AMPR receptor subunits during late mild cognitive impairment compared to men at the same point in the progression of AD (Counts et al., 2011). Reduced levels of GluA2-containing AMPR receptor subunits could result in a greater proportion of GluA2-lacking, Ca2+-permeable AMPA receptors, and thus, increased vulnerability to excitotoxicity due to increased calcium conductance (Counts et al., 2011). To date, there are no studies that have examined whether glutamatergic drug treatments for AD exhibit similar effectiveness in men and women (Canevelli et al., 2017). Future work examining these sex differences in treatment response could provide insight into mechanistic differences in AD progression in men and women.
Just as sex differences are seen in patients with AD, sex differences are observed in AD phenotypes in mouse models of the disease. In the triple transgenic mouse model of AD (3xTg-AD), impairments in spatial memory and inhibitory avoidance tasks appear earlier in female mice than male mice (Clinton et al., 2007). Among 3xTgAD mice, both males and females show deficits in working memory, short-term memory, and increased anxiety-like behavior by 12 months of age, though female mutants show additional impairments in reference memory (Blázquez et al., 2014). This same early onset of cognitive deficits is also seen in two other mouse models of AD, tTa:APPsi mice, in which amyloid precursor protein (APP) expression is driven by the tetracycline transactivator (Melnikova et al., 2016) and APP(SW) mice which overexpress human APP (King et al., 1999). Furthermore, female mice exhibit greater deficits in cognitive function following overexpression of corticotropin releasing factor (CRF) in the presence of human APP compared to males (Bangasser et al., 2017). These differences in behavioral phenotypes are accompanied by differences in pathology. In another AD mouse model, the APP/PS1 transgenic line, female mice show an increase in plasma levels of amyloid protein with age, while males do not (Ordóñez-Gutiérrez et al., 2015). Female APP/PS1 mice also exhibit higher levels of parenchymal Aβ, particularly in the hippocampus, along with higher levels of phosphorylated tau and proinflammatory cytokines compared to male mutant mice (Jiao et al., 2016).
Building upon the work done in clinical studies, preclinical mouse models have found a role for glutamate in AD symptomatology. Learning deficits and amyloid plaque formation are among the AD symptoms implicated by disruptions in the glutamatergic system. Rats given a competitive NMDA receptor blocker showed deficits in reversal learning, yet no changes in the initial acquisition of a spatial memory task (Zhang et al., 2014), suggesting that NMDA receptors are at least partially involved in the learning deficits associated with AD. NMDA receptors have also been examined in mouse models. Treatment with memantine decreases amyloid plaque formation in APP/PS1-21 mice (Scholtzova et al., 2008). However, when treated with memantine, APP/PS1-21 mice performed similarly to WT controls in the object recognition test (Scholtzova et al., 2008). GluCEST and 1H MRS imaging of the APP-PS1 mouse model showed decreased glutamate levels throughout the brain (compared to WT controls), but the largest difference was observed in the hippocampus (Haris et al., 2013). This suggests that glutamate, and especially NMDA receptors, may be involved in the pathogenesis of AD (Monfort et al., 2015).
Furthermore, glutamatergic sex differences have been observed in preclinical models of AD. Reductions in glutamate within the dorsal hippocampus are seen only in male McGill-R-Thy1-APP rats and not females (Nilsen et al., 2014). Sex differences in AD development could be due to an interaction of glutamatergic systems with sex hormones. Estrogen is thought to play a protective role against cognitive impairments in female, and potentially male, rodents (Li C. et al., 2004; Frye et al., 2005; Carroll et al., 2007). It is hypothesized that estrogen is an underlying factor of sex differences in cognitive deficits following stress in rodents (Luine et al., 2007). After repeated stress, female rats show normal PFC glutamatergic transmission (Wei et al., 2014), suggesting that estrogen may be protective of PFC-mediated functioning. Furthermore, E2 treatment ameliorates Aβ-induced deficits in synaptic plasticity (Logan et al., 2011). However, as women age, their estrogen levels decline and this decline in estrogen may increase vulnerability (Barron and Pike, 2012). To date, the studies done in mouse and rat models of AD have not taken declining estrogen levels into account.
Major Depressive Disorder
Women are nearly twice as likely as men to develop MDD and among those diagnosed with MDD, women experience more severe symptoms than men (Kornstein et al., 1995). Although the efficacy of SSRIs has focused the depression field on the serotonergic system, recent work on the efficacy of ketamine in treating MDD has led to increased interest in the glutamatergic system (Berman et al., 2000). Individuals with MDD have lower levels of both glutamate and glutamine in several brain regions including the ACC, dorsolateral prefrontal cortex (dlPFC), dorsomedial amygdala, and hippocampus (Auer et al., 2000; Michael et al., 2003a,b; Block et al., 2009). While the majority of studies have found this relationship, a few studies have not detected differences in glutamate metabolites (either glutamate or glutamine) in MDD (Binesh et al., 2004; Milne et al., 2009; Price et al., 2009). It is possible that some of the disparities in findings regarding glutamate levels and MDD are due to inconsistencies among participants between studies i.e., the ratio of men to women in the study and whether women were pre- or post- menopause (Gray et al., 2015). However, to date, none of these studies have examined potential sex differences in glutamate metabolite levels in MDD patients. Women with MDD have been shown to have higher levels of glutamate receptor gene expression postmortem, particularly in both AMPA and NMDA receptor subunit expression Additionally, women with postpartum depression exhibit an increase in prefrontal glutamate compared to healthy controls (McEwen et al., 2012). Thus, there is evidence for increased dysregulation in the glutamate system in women with MDD.
Similar to what has been seen in the clinical population, increased activity in the glutamatergic system has been connected to depression-like behavior in preclinical models. Male rats from the Flinders sensitive line (FSL), a model of depression, exhibit increased glutamatergic synaptic transmission in the hippocampus compared to controls (Gómez-Galán et al., 2013). However, female FSL rats exhibit higher levels of glutamate within the PFC compared to their male FSL counterparts (Kokras et al., 2009). Female rats also exhibit an increase in glutamate in the PFC in response to acute stress whereas males do not (Kokras et al., 2018). Furthermore, antidepressant administration increases cortical glutamate levels in both male and female FSL rats, while only increasing hippocampal glutamate in females (Kokras et al., 2009). Female rats expressing learned helplessness behavior, similarly would have increased glutamate, because they exhibit decreased glutamate uptake in the hippocampus, cortex, and striatum (Almeida et al., 2010). Furthermore, genetic alterations in the glutamate system can lead to depressive symptoms. Decreasing levels of vesicular glutamate transporter with a heterozygous knockout (VGLUT1+/−) leads to depressive-like behavior in mice (Tordera et al., 2011). However, chronic mild stress, another model of depression, leads to increased VGLUT1 levels in the hippocampus suggesting that bidirectional dysregulation of the glutamate system can be associated with depressive phenotypes (Garcia-Garcia et al., 2009).
Along with these broad differences in the glutamate system, preclinical models have revealed sex-specific alterations in the glutamate system in models of depression. Following prenatal chronic mild stress, male rats displayed higher expression of mGluR2/3, mGluR5, and NR1 in the prefrontal cortex; while female rats did not (Wang et al., 2015). Neonatal NMDA receptor blockade increases both physiological stress responsivity, CORT response, and anxiety-like behavior in the elevated plus maze in adult male mice, while female mice exhibit a decreased in anxiety-like behavior following the same treatment (Amani et al., 2013). Although the glutamate system of males appears more vulnerable to manipulations early in life, in adulthood, female mice are more sensitive to the antidepressant effects of ketamine, an NMDA receptor antagonist (Carrier and Kabbaj, 2013). Female mice exhibit a decrease in immobility in the forced swim test as well as an antidepressant response in the novelty suppressed feeding test at doses of ketamine that have no effect in males (Carrier and Kabbaj, 2013). These studies suggest that adult female mice have increased glutamate tone on NMDA receptors that may be leading to increased anxiety and depressive-like behaviors. This increased NMDA receptor tone may be responsible for the increased hippocampal dendritic spine density in females at baseline (Woolley et al., 1990; Shors et al., 2004). This idea is supported by work demonstrating that male and female rats exhibit opposite spine density changes in response to acute stress and these different responses are mediated by NMDA receptor activation (Shors et al., 2004). Further, this could provide a mechanism by which females are hyper-responsive to anxiety provoking stimuli in their environment.
Schizophrenia
In contrast to AD and MDD, SCZ is more prevalent in men, with a male to female ratio of ~1.4:1.0 (Castle et al., 1993). Furthermore, men exhibit an earlier age of onset, greater symptom severity, and poorer response to treatment (Abel et al., 2010). Although there are many factors contributing to these sex differences, differences in the glutamatergic system are a critical component. Impairments in the glutamatergic system contribute to the pathophysiology of SCZ. (Olney and Farber, 1995; Goff and Coyle, 2001; Coyle et al., 2002; Tsai and Coyle, 2002; Javitt, 2007). However, this contribution appears to be different in men and women. For example, polymorphisms in different glutamate related genes increase the risk for SCZ in males and females. Multiple single-nucleotide polymorphisms (SNPs) in an X-linked gene coding for the AMPA receptor subunit 3, GRIA3, confer increased risk for the development of SCZ in females only (Magri et al., 2008). On the other hand, SNPs in the SAP97 gene that encodes a scaffolding protein involved in membrane targeting of glutamate receptors, is associated with an increased risk of SCZ in males but not females (Uezato et al., 2012).
Along with differences in genetic contributions, sex differences in glutamate related protein expression and metabolites have been found. Glutamine synthetase, an enzyme involved in the maintenance of glutamate levels, is upregulated in women with SCZ but not men (Martins-de-Souza et al., 2010). Additionally, women with SCZ exhibit higher levels of NMDA receptor density compared to men with SCZ (Nudmamud-Thanoi and Reynolds, 2004). NMDA receptor hypofunction is hypothesized to contribute to the pathophysiology of SCZ, therefore increased NMDA receptor density in women with SCZ could be protective and contribute to sex differences in symptomology (Leung and Chue, 2000; Coyle et al., 2002).
Examinations of sex differences in preclinical models of SCZ are few and far between. Much of the research on SCZ has focused on behavioral endophenotypes. Prepulse inhibition of startle (PPI), the reduction of startle produced by a prepulse stimulus, is diminished in patients with SCZ and can be easily modeled in animals (Swerdlow and Geyer, 1998). Female rats exhibit higher levels of PPI compared to males at baseline (Nozari et al., 2015; Zhang X. et al., 2015; Gogos et al., 2017). NMDA receptor antagonist, MK-801, decreases PPI in both intact and gonadectomized male mice whereas female mice only exhibit this decrease following ovariectomy (van den Buuse et al., 2017). This suggests that circulating hormones protect females against NMDA receptor mediated disruption of PPI. In support of this, estradiol treatment following ovariectomy blunts the ability of MK-801 to disrupt PPI (Gogos et al., 2012). Higher doses of MK-801 are able to disrupt PPI in females suggesting that NMDA receptors are still involved in the response in both sexes (Nozari et al., 2015).
In contrast to these static models of behavioral endophenotypes, developmental animal models of SCZ, such as the neonatal hippocampal lesion (nVHL) model, mimic the developmental progression of the disorder. The initial studies describing the nVHL model and the majority of those since then have utilized only the male pups, eliminating the ability to determine whether any sex differences exist (Lipska et al., 1993; Chambers et al., 1996; Flores et al., 1996; Goto and O'Donnell, 2002). An analysis of the literature revealed three papers that examined both males and females after nVHL. Overall, many of the behavioral effects of nVHL are similar in males and females, including deficits in working memory and increased locomotor response to novelty, MK-801 and amphetamine (Beninger et al., 2009; Bychkov et al., 2011). However, following nVHL, male mice exhibit hyperactivity in response to apomorphine, a non-selective dopamine agonist, whereas females do not (Bychkov et al., 2011). Further, following nVHL only male mice exhibit a decrease in phosphorylated extracellular signal-related kinase (pERK), mitrogen activated protein kinase (pMAPK), glycogen synthase kinase 3β (pGSK-3β), and protein kinase B (pAkt) in the accumbens and pERK within the PFC (Bychkov et al., 2011). In contrast, only female mice exhibit a decrease in pAkt and pMAPK in the dorsal striatum following nVHL (Bychkov et al., 2011). Along with these behavioral and molecular sex differences, there are also sex differences in the response to antipsychotics following nVHL. Clozapine can worsen working memory deficits in male nVHL mice whereas a floor effect may limit its effects in female nVHL mice (Levin and Christopher, 2006). However, control females are vulnerable to the memory dampening effects of clozapine whereas males are not (Levin and Christopher, 2006). Along with the nVHL model, neonatal administration of an NMDA receptor antagonist also induces SCZ-like behavior (Stefani and Moghaddam, 2005). However, the SCZ-like phenotypes are influenced by sex and hormonal status, with males and diestrous females exhibiting more consistent endophenotypes compared to proestrous females (Célia Moreira Borella et al., 2016). This could reflect a protective effect of estrogens, as levels of estradiol are highest during proestrus.
Studies utilizing mutant mice have also revealed sex differences that may be relevant to SCZ. The gene neuregulin1 (NRG1) confers an increased risk of SCZ and mutations in NRG1 lead to SCZ-like endophenotypes in mice (Gerlai et al., 2000; Stefansson et al., 2002, 2003, 2004; Li T. et al., 2004). However, there are sex differences in these phenotypes. While male neuregulin deficient mice exhibit deficits in object recognition memory and both contextual and cued fear conditioning, female Nrg1+/− mice do not exhibit any cognitive deficits (Pei et al., 2014). Additionally, male Nrg1+/− mice exhibited a decrease in the GABAergic markers, GAD67 and parvalbumin, while females did not (Pei et al., 2014). Although both male and female NRG1 mutant mice exhibit an increase in exploratory behavior, the specific elements of this behavior differed between males and female mutants (O'Tuathaigh et al., 2006).
Abnormalities in glutamatergic functioning have been associated with SCZ-like symptoms in animals. NMDA receptor hypofunction has been repeatedly cited as a component of SCZ and D-serine, an NMDA receptor co-agonist, may have therapeutic effects (Labrie et al., 2012). Accordingly, disrupting the glutamate system in a variety of ways, including neonatal NMDA antagonism (Stefani and Moghaddam, 2005) or deletion of AMPA GluA1 subunits (Procaccini et al., 2013), can lead to behavioral symptoms of the disease. Neonatal VHL rats also display disruptions in glutamate signaling, with reduced glutamate release in the PFC (Beninger et al., 2009). Furthermore, PCP and MK-801, NMDA receptor antagonists, have long been used to model the positive symptoms of SCZ (Moghaddam and Jackson, 2003). Perinatal treatment with PCP leads to deficits in spatial reference memory in male rats but not females (Andersen and Pouzet, 2004). Furthermore, these deficits were alleviated by treatment with D-serine, an NMDA co-agonist, suggesting that males may be more sensitive to disruptions of NMDA function than females (Andersen and Pouzet, 2004). Copy number variants (CNV) in the synaptic scaffolding molecular (S-SCAM), which controls synaptic AMPA receptor levels, have been linked to risk for SCZ. Transgenic mice with S-SCAM CNVs exhibit behaviors consistent with positive, negative, and cognitive symptoms of SCZ, as well as cellular and morphological abnormalities (Zhang N. et al., 2015). These mice also mimic the human condition because although both males and females show SCZ-like symptoms, male S-SCAM Tg mice generally exhibit more severe symptoms (Zhang N. et al., 2015). Taken together these findings suggest that increased glutamatergic tone in females may be protective and lead to differences in symptomology.
Autism Spectrum Disorder
Similar to the sex bias seen in SCZ, ASD is more common in boys, affecting nearly four times as many boys as it does girls (Fombonne, 2009; Elsabbagh et al., 2012). Individuals with ASD have decreased levels of glutamate metabolites in the basal ganglia and ACC and these decreases are correlated with severity of ASD symptoms (Horder et al., 2013; Tebartz van Elst et al., 2014). In contrast to these decreases in glutamate metabolites in the brain, children with ASD have increased levels of glutamate in plasma and these levels also correlate with symptom severity (Cai et al., 2016). Despite the clear sex bias in the disease, to date, no studies have examined sex differences in metabolite levels (Ford and Crewther, 2016).
Similar to animal models of SCZ, animal models of autism focus on endophenotypes. In particular, autism-like behaviors in rodents have focused on deficits in social behavior. Healthy juvenile male mice exhibit more social exploratory behavior compared to juvenile females (Karlsson et al., 2015; Netser et al., 2017). Following prenatal valproic acid (VPA) treatment, an animal model of autism, male mice show impairments in social behavior in adulthood, while female mice do not (Kim et al., 2013). The prenatal VPA model also leads to male-specific deficits in sensorimotor gating, another phenotype of ASD (Anshu et al., 2017). Similar male-specific effects are seen in the telomerase reverse transcriptase overexpressing mice (TERT-tg). Male TERT-tg mice exhibit impaired social behavior, increased anxiety-like behavior, and lowered seizure threshold, while female TERT-tg mice do not (Kim et al., 2017). Maternal immune challenge also leads to male-specific deficits in social behavior in the contactin-associated protein-like 2 (Cntnap2) mouse model of ASD (Schaafsma et al., 2017). Individuals with ASD exhibit a decrease in striatal activation in response to social and non-social rewards (Scott-Van Zeeland et al., 2010). Male-specific deficits in reward learning are seen following 16p11.2 hemideletion, a gene that is disrupted in ASD (Weiss et al., 2008; Grissom et al., 2018).
Consistent with what has been seen in patients with ASD, preclinical studies demonstrate a clear role for the glutamate system in ASD-like behaviors. Extracellular glutamate concentrations in the lateral septum (LS) increase during social play for both male and female juvenile rats (Bredewold et al., 2015). In a mouse model of a common CNV found in ASD, ubiquitin protein ligase Ube3a, shows deficits in social interaction, impaired communication, and increased incidence of repetitive behaviors are accompanied by impaired glutamate synaptic transmission in male and female mice (Smith et al., 2011). A similar relationship is seen in both male and female Shank2 knockout mice. These mice show reduced social interaction and communication, impaired spatial learning and memory, and increased anxiety-like behavior, which are accompanied by reductions in NMDA receptor function (Won et al., 2012). Furthermore, restoring NMDA receptor function with D-cycloserine reversed the decreased sociability phenotype (Won et al., 2012). However, disruption of Shank3, another gene implicated in human ASD patients, leads to more pronounced reductions in glutamate transmission in male knockout mice and only juvenile males exhibit deficits in social behavior (Yang et al., 2012). As male mice exhibit higher levels of glutamate induced by social play compared to females, there may be sex differences in sensitivity to perturbations in the glutamate system (Bredewold et al., 2015). Furthermore, the increase in glutamatergic tone may be protective in females.
Attention Deficit Hyperactivity Disorder (ADHD)
Attention deficit hyperactivity disorder (ADHD) also shows a strong male bias, affecting nearly 3 times as many boys as girls (Cuffe et al., 2005). Traditionally mechanistic work on ADHD has focused on catecholamine function due to the therapeutic efficacy of stimulants. However, more recently the focus has shifted to the glutamate system due to data from genetic screenings implicating CNVs and SNPs in multiple glutamate receptor subtypes (Turic et al., 2004, 2005; Lesch et al., 2008; Mick et al., 2008; Elia et al., 2011). Furthermore, MRS imaging studies show increased glutamatergic tone in both the frontal cortex and striatum of ADHD patients and this is normalized by pharmacological treatment (Carrey et al., 2003; MacMaster et al., 2003). While no studies have examined male and female ADHD patients and made direct comparisons, female ADHD patients exhibit a positive correlation between ACC glutamate concentration and impulsivity (Ende et al., 2016). Glutamate may play a role in not only the pathology associated with ADHD but also the treatment response. Polymorphisms in NDMA receptor subunit genes predict better methylphenidate treatment response in children with ADHD (Kim et al., 2016). Notably, while studies discussed above controlled for sex, none of the published clinical studies have examined the influence of sex as an independent variable.
The majority of the work examining animal models of ADHD have either utilized only male mice to assess phenotypes (Archer et al., 1988; Kuwagata and Nagao, 1998; Kuwagata et al., 2004; Mergy et al., 2014) or in many cases where males and females were used data were collapsed preventing any examination of possible sex differences (Shaywitz et al., 1976, 1977; Pappas et al., 1980; Dell'Anna et al., 1991; Row et al., 2002). However, some studies utilizing the spontaneous hypertensive rat (SHR) model of ADHD have reported sex differences in behavioral phenotypes. Notably, while both male and female SHRs showed hyperactivity and sustained attention deficits, male SHRs exhibit greater impulsivity (Berger and Sagvolden, 1998). While there is evidence that male SHRs perform better on conditioned association tasks than female SHRs, this seems to reflect an increase in performance compared to controls in the males rather than a decrement in females (Bucci et al., 2008). Direct comparisons between controls and SHR males and females revealed attention deficits in male SHR rats that were not present in female SHRs, while both sexes exhibited increased inhibitory control and hyperactivity (Bayless et al., 2015). Along with these differences in behavioral phenotypes, animal models have also revealed sex differences in treatment response. Omega-3 polyunsaturated fatty acid supplementation lead to improved reinforcement-controlled attention in male SHRs while not affecting female SHRs (Dervola et al., 2012). These findings may be explained by the effects of sex hormones on fatty acid metabolism, particularly the low level of alpha-linolenic acid to docosahexaenoic acid metabolism in males (Dervola et al., 2012).
Just as alterations in the glutamate system have been implicated in human ADHD patients, animal models of ADHD also exhibit aberrant glutamatergic signaling. SHRs exhibit higher levels of glutamate-evoked norepinephrine release and slower AMPR receptor internalization within the hippocampus compared to controls (Howells and Russell, 2008). Given that there is evidence for increased extracellular glutamate within the hippocampus, these downstream effects could be even greater than they appear (Sterley et al., 2016). This increase in extracellular glutamate may occur outside the hippocampus as well. SHR males have heightened levels of evoked glutamate release in the PFC and striatum compared to controls (Miller et al., 2014). Furthermore, manipulations of the glutamate system can lead to ADHD-like behaviors. Infusion of the NMDA antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid, into the mPFC of rats leads to increased impulsivity and compulsivity (Pozzi et al., 2011). Despite this link between glutamate and ADHD behavioral phenotypes and the observed sex differences in preclinical models, differential roles of glutamate or alterations in the glutamate system have not been examined in sex-specific manner.
Conclusion
These studies clearly demonstrate a role for dysregulation in the glutamate system in sex biased psychiatric diseases. The little data that are available suggest that females have increased glutamatergic tone compared to males and this can increase vulnerability in some cases and be protective in others. However, very little work has been done to elucidate potential sex differences in the glutamate system either at baseline or in the disease state (see Table 1). Although more imaging and postmortem tissue analysis in clinical populations would be insightful, a basic understanding of sex differences in glutamate signaling is needed. To achieve this, more preclinical studies aimed at determining sex differences are warranted. After a fundamental understanding of baseline differences is reached, examination of how dysfunction in the glutamate system can contribute to psychiatric disease would be more informative. As the majority of preclinical work has been done either only in male rodents or studies that have been underpowered to examine sex differences, much of what we know about glutamate system function and psychiatric disease may only apply to males. The examination of how glutamate dysfunction differentially affects males and females could lead to novel avenues for therapeutic development in these sex biased diseases.
Table 1. Sex differences in glutamate systems in disease.
Author Contributions
MW, DB, and LB contributed to the conception and design of this review, and edited and revised the manuscript. MW and LB wrote the manuscript. MW, DB, and LB have seen and approve of the final version to be published.
Funding
This work was supported by National Institute on Drug Abuse (NIDA) Grant R00 DA033372 (LB), Grant T32 DA007237 (MW), National Science Foundation NSF CAREER IOS-1552416 to (DB) and a Brain & Behavior Research Foundation NARSAD award (LB).
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Abel, K. M., Drake, R., and Goldstein, J. M. (2010). Sex differences in schizophrenia. Int. Rev. Psychiatry 22, 417–428. doi: 10.3109/09540261.2010.515205
Almeida, R. F., Thomazi, A. P., Godinho, G. F., Saute, J. A., Wofchuk, S. T., Souza, D. O., et al. (2010). Effects of depressive-like behavior of rats on brain glutamate uptake. Neurochem. Res. 35, 1164–1171. doi: 10.1007/s11064-010-0169-4
Amani, M., Samadi, H., Doosti, M. H., Azarfarin, M., Bakhtiari, A., Majidi-Zolbanin, N., et al. (2013). Neonatal NMDA receptor blockade alters anxiety- and depression-related behaviors in a sex-dependent manner in mice. Neuropharmacology 73, 87–97. doi: 10.1016/j.neuropharm.2013.04.056
Andersen, J. D., and Pouzet, B. (2004). Spatial memory deficits induced by perinatal treatment of rats with PCP and reversal effect of D-serine. Neuropsychopharmacology 29, 1080–1090. doi: 10.1038/sj.npp.1300394
Anshu, K., Nair, A. K., Kumaresan, U. D., Kutty, B. M., Srinath, S., and Laxmi, T. R. (2017). Altered attentional processing in male and female rats in a prenatal valproic acid exposure model of autism spectrum disorder. Autism Res. 10, 1929–1944. doi: 10.1002/aur.1852
Archer, T., Danysz, W., Fredriksson, A., Jonsson, G., Luthman, J., Sundstrom, E., et al. (1988). Neonatal 6-hydroxydopamine-induced dopamine depletions: motor activity and performance in maze learning. Pharmacol. Biochem. Behav. 31, 357–364. doi: 10.1016/0091-3057(88)90358-9
Auer, D. P., Putz, B., Kraft, E., Lipinski, B., Schill, J., and Holsboer, F. (2000). Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol. Psychiatry 47, 305–313. doi: 10.1016/S0006-3223(99)00159-6
Bangasser, D. A., Dong, H., Carroll, J., Plona, Z., Ding, H., Rodriguez, L., et al. (2017). Corticotropin-releasing factor overexpression gives rise to sex differences in Alzheimer's disease-related signaling. Mol. Psychiatry 22, 1126–1133. doi: 10.1038/mp.2016.185
Barron, A. M., and Pike, C. J. (2012). Sex hormones, aging, and Alzheimer's disease. Front. Biosci. 4, 976–997.
Bayless, D. W., Perez, M. C., and Daniel, J. M. (2015). Comparison of the validity of the use of the spontaneously hypertensive rat as a model of attention deficit hyperactivity disorder in males and females. Behav. Brain Res. 286, 85–92. doi: 10.1016/j.bbr.2015.02.029
Beninger, R. J., Tuerke, K. J., Forsyth, J. K., Giles, A., Xue, L., Boegman, R. J., et al. (2009). Neonatal ventral hippocampal lesions in male and female rats: effects on water maze, locomotor activity, plus-maze and prefrontal cortical GABA and glutamate release in adulthood. Behav. Brain Res. 202, 198–209. doi: 10.1016/j.bbr.2009.03.044
Berger, D. F., and Sagvolden, T. (1998). Sex differences in operant discrimination behaviour in an animal model of attention-deficit hyperactivity disorder. Behav. Brain Res. 94, 73–82. doi: 10.1016/S0166-4328(97)00171-X
Berman, R. M., Cappiello, A., Anand, A., Oren, D. A., Heninger, G. R., Charney, D. S., et al. (2000). Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 47, 351–354. doi: 10.1016/S0006-3223(99)00230-9
Binesh, N., Kumar, A., Hwang, S., Mintz, J., and Thomas, M. A. (2004). Neurochemistry of late-life major depression: a pilot two-dimensional MR spectroscopic study. J. Magn. Reson. Imaging 20, 1039–1045. doi: 10.1002/jmri.20214
Blázquez, G., Cañete, T., Tobeña, A., Giménez-Llort, L., and Fernández-Teruel, A. (2014). Cognitive and emotional profiles of aged Alzheimer's disease (3 × TgAD) mice: effects of environmental enrichment and sexual dimorphism. Behav. Brain Res. 268, 185–201. doi: 10.1016/j.bbr.2014.04.008
Block, W., Traber, F., Von Widdern, O., Metten, M., Schild, H., Maier, W., et al. (2009). Proton MR spectroscopy of the hippocampus at 3 T in patients with unipolar major depressive disorder: correlates and predictors of treatment response. Int. J. Neuropsychopharmacol. 12, 415–422. doi: 10.1017/S1461145708009516
Bredewold, R., Schiavo, J. K., van Der Hart, M., Verreij, M., and Veenema, A. H. (2015). Dynamic changes in extracellular release of GABA and glutamate in the lateral septum during social play behavior in juvenile rats: implications for sex-specific regulation of social play behavior. Neuroscience 307, 117–127. doi: 10.1016/j.neuroscience.2015.08.052
Bucci, D. J., Hopkins, M. E., Keene, C. S., Sharma, M., and Orr, L. E. (2008). Sex differences in learning and inhibition in spontaneously hypertensive rats. Behav. Brain Res. 187, 27–32. doi: 10.1016/j.bbr.2007.08.022
Bychkov, E., Ahmed, M. R., and Gurevich, E. V. (2011). Sex differences in the activity of signalling pathways and expression of G-protein-coupled receptor kinases in the neonatal ventral hippocampal lesion model of schizophrenia. Int. J. Neuropsychopharmacol. 14, 1–15. doi: 10.1017/S1461145710000118
Cai, J., Ding, L., Zhang, J. S., Xue, J., and Wang, L. Z. (2016). Elevated plasma levels of glutamate in children with autism spectrum disorders. Neuroreport 27, 272–276. doi: 10.1097/WNR.0000000000000532
Canevelli, M., Quarata, F., Remiddi, F., Lucchini, F., Lacorte, E., Vanacore, N., et al. (2017). Sex and gender differences in the treatment of Alzheimer's disease: a systematic review of randomized controlled trials. Pharmacol. Res. 115, 218–223. doi: 10.1016/j.phrs.2016.11.035
Carrey, N., MacMaster, F. P., Fogel, J., Sparkes, S., Waschbusch, D., Sullivan, S., et al. (2003). Metabolite changes resulting from treatment in children with ADHD: a 1H-MRS study. Clin. Neuropharmacol. 26, 218–221. doi: 10.1097/00002826-200307000-00013
Carrier, N., and Kabbaj, M. (2013). Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology 70, 27–34. doi: 10.1016/j.neuropharm.2012.12.009
Carroll, J. C., Rosario, E. R., Chang, L., Stanczyk, F. Z., Oddo, S., Laferla, F. M., et al. (2007). Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice. J. Neurosci. 27, 13357–13365. doi: 10.1523/JNEUROSCI.2718-07.2007
Castle, D. J., Wessely, S., and Murray, R. M. (1993). Sex and schizophrenia: effects of diagnostic stringency, and associations with and premorbid variables. Br. J. Psychiatry 162, 658–664. doi: 10.1192/bjp.162.5.658
Célia Moreira Borella, V., Seeman, M. V., Carneiro Cordeiro, R., Vieira Dos Santos, J., Romario Matos de Souza, M., Nunes de Sousa Fernandes, E., et al. (2016). Gender and estrous cycle influences on behavioral and neurochemical alterations in adult rats neonatally administered ketamine. Dev. Neurobiol. 76, 519–532. doi: 10.1002/dneu.22329
Chambers, R. A., Moore, J., McEvoy, J. P., and Levin, E. D. (1996). Cognitive effects of neonatal hippocampal lesions in a rat model of schizophrenia. Neuropsychopharmacology 15, 587–594. doi: 10.1016/S0893-133X(96)00132-7
Chiu, P. W., Lui, S. S. Y., Hung, K. S. Y., Chan, R. C. K., Chan, Q., Sham, P. C., et al. (2018). In vivo gamma-aminobutyric acid and glutamate levels in people with first-episode schizophrenia: a proton magnetic resonance spectroscopy study. Schizophr. Res. 193, 295–303. doi: 10.1016/j.schres.2017.07.021
Choi, K. H., Zepp, M. E., Higgs, B. W., Weickert, C. S., and Webster, M. J. (2009). Expression profiles of schizophrenia susceptibility genes during human prefrontal cortical development. J. Psychiatry Neurosci. 34, 450–458.
Clinton, L. K., Billings, L. M., Green, K. N., Caccamo, A., Ngo, J., Oddo, S., et al. (2007). Age-dependent sexual dimorphism in cognition and stress response in the 3xTg-AD mice. Neurobiol. Dis. 28, 76–82. doi: 10.1016/j.nbd.2007.06.013
Counts, S. E., Che, S., Ginsberg, S. D., and Mufson, E. J. (2011). Gender differences in neurotrophin and glutamate receptor expression in cholinergic nucleus basalis neurons during the progression of Alzheimer's disease. J. Chem. Neuroanat. 42, 111–117. doi: 10.1016/j.jchemneu.2011.02.004
Coyle, J. T., Tsai, G., and Goff, D. C. (2002). Ionotropic glutamate receptors as therapeutic targets in schizophrenia. Curr. Drug Targets CNS Neurol. Disord. 1, 183–189. doi: 10.2174/1568007024606212
Cuffe, S. P., Moore, C. G., and McKeown, R. E. (2005). Prevalence and correlates of ADHD symptoms in the national health interview survey. J. Atten. Disord. 9, 392–401. doi: 10.1177/1087054705280413
Dell'Anna, M. E., Calzolari, S., Molinari, M., Iuvone, L., and Calimici, R. (1991). Neonatal anoxia induces transitory hyperactivity, permanent spatial memory deficits and CA1 cell density reduction in developing rats. Behav. Brain Res. 45, 125–134. doi: 10.1016/S0166-4328(05)80078-6
Dervola, K. S., Roberg, B. A., Woien, G., Bogen, I. L., Sandvik, T. H., Sagvolden, T., et al. (2012). Marine omicron-3 polyunsaturated fatty acids induce sex-specific changes in reinforcer-controlled behaviour and neurotransmitter metabolism in a spontaneously hypertensive rat model of ADHD. Behav. Brain Funct. 8:56. doi: 10.1186/1744-9081-8-56
Domingues, A., Almeida, S., da Cruz E Silva, E. F., Oliveira, C. R., and Rego, A. C. (2007). Toxicity of beta-amyloid in HEK293 cells expressing NR1/NR2A or NR1/NR2B N-methyl-D-aspartate receptor subunits. Neurochem. Int. 50, 872–880. doi: 10.1016/j.neuint.2007.03.001
Duarte, J. M., Do, K. Q., and Gruetter, R. (2014). Longitudinal neurochemical modifications in the aging mouse brain measured in vivo by 1H magnetic resonance spectroscopy. Neurobiol. Aging 35, 1660–1668. doi: 10.1016/j.neurobiolaging.2014.01.135
Elia, J., Glessner, J. T., Wang, K., Takahashi, N., Shtir, C. J., Hadley, D., et al. (2011). Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nat. Genet. 44, 78–84. doi: 10.1038/ng.1013
Elsabbagh, M., Divan, G., Koh, Y. J., Kim, Y. S., Kauchali, S., Marcin, C., et al. (2012). Global prevalence of autism and other pervasive developmental disorders. Autism Res. 5, 160–179. doi: 10.1002/aur.239
Ende, G., Cackowski, S., van Eijk, J., Sack, M., Demirakca, T., Kleindienst, N., et al. (2016). Impulsivity and aggression in female BPD and ADHD patients: association with ACC glutamate and GABA concentrations. Neuropsychopharmacology 41, 410–418. doi: 10.1038/npp.2015.153
Ferreira, J. S., Papouin, T., Ladepeche, L., Yao, A., Langlais, V. C., Bouchet, D., et al. (2017). Co-agonists differentially tune GluN2B-NMDA receptor trafficking at hippocampal synapses. Elife 6:e25492. doi: 10.7554/eLife.25492
Flores, G., Barbeau, D., Quirion, R., and Srivastava, L. K. (1996). Decreased binding of dopamine D3 receptors in limbic subregions after neonatal bilateral lesion of rat hippocampus. J. Neurosci. 16, 2020–2026. doi: 10.1523/JNEUROSCI.16-06-02020.1996
Fombonne, E. (2005). The changing epidemiology of autism. J. Appl. Res. Intell. Disabilit. 18, 281–294. doi: 10.1111/j.1468-3148.2005.00266.x
Fombonne, E. (2009). Epidemiology of pervasive developmental disorders. Pediatr. Res. 65, 591–598. doi: 10.1203/PDR.0b013e31819e7203
Ford, T. C., and Crewther, D. P. (2016). A comprehensive review of the (1)H-MRS metabolite spectrum in autism spectrum disorder. Front. Mol. Neurosci. 9:14. doi: 10.3389/fnmol.2016.00014
Frankfurt, M., Fuchs, E., and Wuttke, W. (1984). Sex differences in gamma-aminobutyric acid and glutamate concentrations in discrete rat brain nuclei. Neurosci. Lett. 50, 245–250. doi: 10.1016/0304-3940(84)90493-2
Frye, C. A., Rhodes, M. E., and Dudek, B. (2005). Estradiol to aged female or male mice improves learning in inhibitory avoidance and water maze tasks. Brain Res. 1036, 101–108. doi: 10.1016/j.brainres.2004.12.014
Garcia-Garcia, A. L., Elizalde, N., Matrov, D., Harro, J., Wojcik, S. M., Venzala, E., et al. (2009). Increased vulnerability to depressive-like behavior of mice with decreased expression of VGLUT1. Biol. Psychiatry 66, 275–282. doi: 10.1016/j.biopsych.2009.02.027
Gerlai, R., Pisacane, P., and Erickson, S. (2000). Heregulin, but not ErbB2 or ErbB3, heterozygous mutant mice exhibit hyperactivity in multiple behavioral tasks. Behav. Brain Res. 109, 219–227. doi: 10.1016/S0166-4328(99)00175-8
Goff, D. C., and Coyle, J. T. (2001). The emerging role of glutamate in the pathophysiology and treatment of schizophrenia. Am. J. Psychiatry 158, 1367–1377. doi: 10.1176/appi.ajp.158.9.1367
Gogos, A., Kusljic, S., Thwaites, S. J., and van den Buuse, M. (2017). Sex differences in psychotomimetic-induced behaviours in rats. Behav. Brain Res. 322, 157–166. doi: 10.1016/j.bbr.2017.01.028
Gogos, A., Kwek, P., and van den Buuse, M. (2012). The role of estrogen and testosterone in female rats in behavioral models of relevance to schizophrenia. Psychopharmacology 219, 213–224. doi: 10.1007/s00213-011-2389-y
Gómez-Galán, M., de Bundel, D., van Eeckhaut, A., Smolders, I., and Lindskog, M. (2013). Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression. Mol. Psychiatry 18, 582–594. doi: 10.1038/mp.2012.10
Goto, Y., and O'Donnell, P. (2002). Delayed mesolimbic system alteration in a developmental animal model of schizophrenia. J. Neurosci. 22, 9070–9077. doi: 10.1523/JNEUROSCI.22-20-09070.2002
Grachev, I. D., and Apkarian, A. V. (2000). Chemical heterogeneity of the living human brain: a proton MR spectroscopy study on the effects of sex, age, and brain region. Neuroimage 11, 554–563. doi: 10.1006/nimg.2000.0557
Gray, A. L., Hyde, T. M., Deep-Soboslay, A., Kleinman, J. E., and Sodhi, M. S. (2015). Sex differences in glutamate receptor gene expression in major depression and suicide. Mol. Psychiatry 20, 1057–1068. doi: 10.1038/mp.2015.91
Grissom, N. M., McKee, S. E., Schoch, H., Bowman, N., Havekes, R., O'Brien, W. T., et al. (2018). Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders. Mol. Psychiatry 23, 544–555. doi: 10.1038/mp.2017.184
Hädel, S., Wirth, C., Rapp, M., Gallinat, J., and Schubert, F. (2013). Effects of age and sex on the concentrations of glutamate and glutamine in the human brain. J. Magn. Reson. Imag. 38, 1480–1487. doi: 10.1002/jmri.24123
Hanley, J. G. (2014). Subunit-specific trafficking mechanisms regulating the synaptic expression of Ca(2+)-permeable AMPA receptors. Semin. Cell Dev. Biol. 27, 14–22. doi: 10.1016/j.semcdb.2013.12.002
Haris, M., Nath, K., Cai, K., Singh, A., Crescenzi, R., Kogan, F., et al. (2013). Imaging of glutamate neurotransmitter alterations in Alzheimer's disease. NMR Biomed. 26, 386–391. doi: 10.1002/nbm.2875
Horder, J., Lavender, T., Mendez, M. A., O'Gorman, R., Daly, E., Craig, M. C., et al. (2013). Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study. Transl. Psychiatry 3:e279. doi: 10.1038/tp.2013.53
Howells, F. M., and Russell, V. A. (2008). Glutamate-stimulated release of norepinephrine in hippocampal slices of animal models of attention-deficit/hyperactivity disorder (spontaneously hypertensive rat) and depression/anxiety-like behaviours (Wistar-Kyoto rat). Brain Res. 1200, 107–115. doi: 10.1016/j.brainres.2008.01.033
Javitt, D. C. (2007). Glutamate and schizophrenia: phencyclidine, N-methyl-D-aspartate receptors, and dopamine-glutamate interactions. Int. Rev. Neurobiol. 78, 69–108. doi: 10.1016/S0074-7742(06)78003-5
Jiao, S. S., Bu, X. L., Liu, Y. H., Zhu, C., Wang, Q. H., Shen, L. L., et al. (2016). Sex dimorphism profile of Alzheimer's Disease-type pathologies in an APP/PS1 mouse model. Neurotox. Res. 29, 256–266. doi: 10.1007/s12640-015-9589-x
Karlsson, S. A., Haziri, K., Hansson, E., Kettunen, P., and Westberg, L. (2015). Effects of sex and gonadectomy on social investigation and social recognition in mice. BMC Neurosci. 16:83. doi: 10.1186/s12868-015-0221-z
Kim, J. I., Kim, J. W., Park, J. E., Park, S., Hong, S. B., Han, D. H., et al. (2016). Association of the GRIN2B rs2284411 polymorphism with methylphenidate response in attention-deficit/hyperactivity disorder. J. Psychopharmacol. 31, 1070–1077. doi: 10.1177/0269881116667707
Kim, K. C., Cho, K. S., Yang, S. M., Gonzales, E. L., Valencia, S., Eun, P. H., et al. (2017). Sex differences in autism-like behavioral phenotypes and postsynaptic receptors expression in the prefrontal cortex of TERT transgenic mice. Biomol. Ther. 25, 374–382. doi: 10.4062/biomolther.2016.242
Kim, K. C., Kim, P., Go, H. S., Choi, C. S., Park, J. H., Kim, H. J., et al. (2013). Male-specific alteration in excitatory post-synaptic development and social interaction in pre-natal valproic acid exposure model of autism spectrum disorder. J. Neurochem. 124, 832–843. doi: 10.1111/jnc.12147
King, D. L., Arendash, G. W., Crawford, F., Sterk, T., Menendez, J., and Mullan, M. J. (1999). Progressive and gender-dependent cognitive impairment in the APP(SW) transgenic mouse model for Alzheimer's disease. Behav. Brain Res. 103, 145–162. doi: 10.1016/S0166-4328(99)00037-6
Kokras, N., Antoniou, K., Polissidis, A., and Papadopoulou-Daifoti, Z. (2009). Antidepressants induce regionally discrete, sex-dependent changes in brain's glutamate content. Neurosci. Lett. 464, 98–102. doi: 10.1016/j.neulet.2009.08.011
Kokras, N., Pastromas, N., Papasava, D., de Bournonville, C., Cornil, C. A., and Dalla, C. (2018). Sex differences in behavioral and neurochemical effects of gonadectomy and aromatase inhibition in rats. Psychoneuroendocrinology 87, 93–107. doi: 10.1016/j.psyneuen.2017.10.007
Kornstein, S. G., Schatzberg, A. F., Yonkers, K. A., Thase, M. E., Keitner, G. I., Ryan, C. E., et al. (1995). Gender differences in presentation of chronic major depression. Psychopharmacol. Bull. 31, 711–718.
Kouchiwa, T., Wada, K., Uchiyama, M., Kasezawa, N., Niisato, M., Murakami, H., et al. (2012). Age-related changes in serum amino acids concentrations in healthy individuals. Clin. Chem. Lab. Med. 50, 861–870. doi: 10.1515/cclm-2011-0846
Kulak, A., Duarte, J. M., Do, K. Q., and Gruetter, R. (2010). Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia. J. Neurochem. 115, 1466–1477. doi: 10.1111/j.1471-4159.2010.07051.x
Kuwagata, M., and Nagao, T. (1998). Behavior and reproductive function of rat male offspring treated prenatally with 5-bromo-2'-deoxyuridine. Reprod. Toxicol. 12, 541–549. doi: 10.1016/S0890-6238(98)00037-9
Kuwagata, M., Muneoka, K. T., Ogawa, T., Takigawa, M., and Nagao, T. (2004). Locomotor hyperactivity following prenatal exposure to 5-bromo-2'-deoxyuridine: neurochemical and behavioral evidence of dopaminergic and serotonergic alterations. Toxicol. Lett. 152, 63–71. doi: 10.1016/j.toxlet.2004.03.019
Labrie, V., Wong, A. H., and Roder, J. C. (2012). Contributions of the D-serine pathway to schizophrenia. Neuropharmacology 62, 1484–1503. doi: 10.1016/j.neuropharm.2011.01.030
Lesch, K. P., Timmesfeld, N., Renner, T. J., Halperin, R., Roser, C., Nguyen, T. T., et al. (2008). Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J. Neural Transm. 115, 1573–1585. doi: 10.1007/s00702-008-0119-3
Leung, A., and Chue, P. (2000). Sex differences in schizophrenia, a review of the literature. Acta Psychiatr. Scand. Suppl. 401, 3–38. doi: 10.1111/j.0065-1591.2000.0ap25.x
Levin, E. D., and Christopher, N. C. (2006). Effects of clozapine on memory function in the rat neonatal hippocampal lesion model of schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 30, 223–229. doi: 10.1016/j.pnpbp.2005.10.018
Li, C., Brake, W. G., Romeo, R. D., Dunlop, J. C., Gordon, M., Buzescu, R., et al. (2004). Estrogen alters hippocampal dendritic spine shape and enhances synaptic protein immunoreactivity and spatial memory in female mice. Proc. Natl. Acad. Sci. U.S.A. 101, 2185–2190. doi: 10.1073/pnas.0307313101
Li, T., Stefansson, H., Gudfinnsson, E., Cai, G., Liu, X., Murray, R. M., et al. (2004). Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype. Mol. Psychiatry 9, 698–704. doi: 10.1038/sj.mp.4001485
Lipska, B. K., Jaskiw, G. E., and Weinberger, D. R. (1993). Postpubertal emergence of hyperresponsiveness to stress and to amphetamine after neonatal excitotoxic hippocampal damage: a potential animal model of schizophrenia. Neuropsychopharmacology 9, 67–75. doi: 10.1038/npp.1993.44
Locklear, M. N., Cohen, A. B., Jone, A., and Kritzer, M. F. (2016). Sex differences distinguish intracortical glutamate receptor-mediated regulation of extracellular dopamine levels in the prefrontal cortex of adult rats. Cereb. Cortex 26, 599–610. doi: 10.1093/cercor/bhu222
Logan, S. M., Sarkar, S. N., Zhang, Z., and Simpkins, J. W. (2011). Estrogen-induced signaling attenuates soluble Abeta peptide-mediated dysfunction of pathways in synaptic plasticity. Brain Res. 1383, 1–12. doi: 10.1016/j.brainres.2011.01.038
Luine, V. N., Beck, K. D., Bowman, R. E., Frankfurt, M., and Maclusky, N. J. (2007). Chronic stress and neural function: accounting for sex and age. J. Neuroendocrinol. 19, 743–751. doi: 10.1111/j.1365-2826.2007.01594.x
MacMaster, F. P., Carrey, N., Sparkes, S., and Kusumakar, V. (2003). Proton spectroscopy in medication-free pediatric attention-deficit/hyperactivity disorder. Biol. Psychiatry 53, 184–187. doi: 10.1016/S0006-3223(02)01401-4
Magri, C., Gardella, R., Valsecchi, P., Barlati, S. D., Guizzetti, L., Imperadori, L., et al. (2008). Study on GRIA2, GRIA3 and GRIA4 genes highlights a positive association between schizophrenia and GRIA3 in female patients. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 745–753. doi: 10.1002/ajmg.b.30674
Man, H. Y., Sekine-Aizawa, Y., and Huganir, R. L. (2007). Regulation of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit. Proc. Natl. Acad. Sci. U.S.A. 104, 3579–3584. doi: 10.1073/pnas.0611698104
Markham, J. A. (2012). Sex steroids and schizophrenia. Rev. Endocrine Metab. Disord. 13, 187–207. doi: 10.1007/s11154-011-9184-2
Martins-de-Souza, D., Maccarrone, G., Wobrock, T., Zerr, I., Gormanns, P., Reckow, S., et al. (2010). Proteome analysis of the thalamus and cerebrospinal fluid reveals glycolysis dysfunction and potential biomarkers candidates for schizophrenia. J. Psychiatr. Res. 44, 1176–1189. doi: 10.1016/j.jpsychires.2010.04.014
Mattson, M. P., Cheng, B., Davis, D., Bryant, K., Lieberburg, I., and Rydel, R. E. (1992). beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389. doi: 10.1523/JNEUROSCI.12-02-00376.1992
McDougall, S. A., Moran, A. E., Baum, T. J., Apodaca, M. G., and Real, V. (2017). Effects of ketamine on the unconditioned and conditioned locomotor activity of preadolescent and adolescent rats: impact of age, sex, and drug dose. Psychopharmacology 234, 2683–2696. doi: 10.1007/s00213-017-4660-3
McEwen, A. M., Burgess, D. T., Hanstock, C. C., Seres, P., Khalili, P., Newman, S. C., et al. (2012). Increased glutamate levels in the medial prefrontal cortex in patients with postpartum depression. Neuropsychopharmacology 37, 2428–2435. doi: 10.1038/npp.2012.101
Melnikova, T., Park, D., Becker, L., Lee, D., Cho, E., Sayyida, N., et al. (2016). Sex-related dimorphism in dentate gyrus atrophy and behavioral phenotypes in an inducible tTa:APPsi transgenic model of Alzheimer's disease. Neurobiol. Dis. 96, 171–185. doi: 10.1016/j.nbd.2016.08.009
Ménard, C., Quirion, R., Vigneault, E., Bouchard, S., Ferland, G., El Mestikawy, S., et al. (2015). Glutamate presynaptic vesicular transporter and postsynaptic receptor levels correlate with spatial memory status in aging rat models. Neurobiol. Aging 36, 1471–1482. doi: 10.1016/j.neurobiolaging.2014.11.013
Mergy, M. A., Gowrishankar, R., Davis, G. L., Jessen, T. N., Wright, J., Stanwood, G. D., et al. (2014). Genetic targeting of the amphetamine and methylphenidate-sensitive dopamine transporter: on the path to an animal model of attention-deficit hyperactivity disorder. Neurochem. Int. 73, 56–70. doi: 10.1016/j.neuint.2013.11.009
Michael, N., Erfurth, A., Ohrmann, P., Arolt, V., Heindel, W., and Pfleiderer, B. (2003a). Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. Psychol. Med. 33, 1277–1284. doi: 10.1017/S0033291703007931
Michael, N., Erfurth, A., Ohrmann, P., Arolt, V., Heindel, W., and Pfleiderer, B. (2003b). Neurotrophic effects of electroconvulsive therapy: a proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression. Neuropsychopharmacology 28, 720–725. doi: 10.1038/sj.npp.1300085
Mick, E., Neale, B., Middleton, F. A., McGough, J. J., and Faraone, S. V. (2008). Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet. 147B, 1412–1418. doi: 10.1002/ajmg.b.30865
Mielke, M. M., Vemuri, P., and Rocca, W. A. (2014). Clinical epidemiology of Alzheimer's disease: assessing sex and gender differences. Clin. Epidemiol. 6, 37–48. doi: 10.2147/CLEP.S37929
Miller, E. M., Pomerleau, F., Huettl, P., Gerhardt, G. A., and Glaser, P. E. (2014). Aberrant glutamate signaling in the prefrontal cortex and striatum of the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder. Psychopharmacology 231, 3019–3029. doi: 10.1007/s00213-014-3479-4
Milne, A., MacQueen, G. M., Yucel, K., Soreni, N., and Hall, G. B. (2009). Hippocampal metabolic abnormalities at first onset and with recurrent episodes of a major depressive disorder: a proton magnetic resonance spectroscopy study. Neuroimage 47, 36–41. doi: 10.1016/j.neuroimage.2009.03.031
Moghaddam, B., and Jackson, M. E. (2003). Glutamatergic animal models of schizophrenia. Ann. N.Y. Acad. Sci. 1003, 131–137. doi: 10.1196/annals.1300.065
Monfort, P., Gomez-Gimenez, B., Llansola, M., and Felipo, V. (2015). Gender differences in spatial learning, synaptic activity, and long-term potentiation in the hippocampus in rats: molecular mechanisms. ACS Chem. Neurosci. 6, 1420–1427. doi: 10.1021/acschemneuro.5b00096
Netser, S., Haskal, S., Magalnik, H., and Wagner, S. (2017). A novel system for tracking social preference dynamics in mice reveals sex- and strain-specific characteristics. Mol. Autism 8:53. doi: 10.1186/s13229-017-0169-1
Nilsen, L. H., Melø, T. M., Witter, M. P., and Sonnewald, U. (2014). Early differences in dorsal hippocampal metabolite levels in males but not females in a transgenic rat model of Alzheimer's disease. Neurochem. Res. 39, 305–312. doi: 10.1007/s11064-013-1222-x
Noble, R. E. (2005). Depression in women. Metab. Clin. Exp. 54, 49–52. doi: 10.1016/j.metabol.2005.01.014
Nozari, M., Shabani, M., Farhangi, A. M., Mazhari, S., and Atapour, N. (2015). Sex-specific restoration of MK-801-induced sensorimotor gating deficit by environmental enrichment. Neuroscience 299, 28–34. doi: 10.1016/j.neuroscience.2015.04.050
Nudmamud-Thanoi, S., and Reynolds, G. P. (2004). The NR1 subunit of the glutamate/NMDA receptor in the superior temporal cortex in schizophrenia and affective disorders. Neurosci. Lett. 372, 173–177. doi: 10.1016/j.neulet.2004.09.035
Olney, J. W., and Farber, N. B. (1995). Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 998–1007. doi: 10.1001/archpsyc.1995.03950240016004
Ordóñez-Gutiérrez, L., Antón, M., and Wandosell, F. (2015). Peripheral amyloid levels present gender differences associated with aging in AβPP/PS1 mice. J. Alzheimers. Dis. 44, 1063–1068. doi: 10.3233/JAD-141158
O'Tuathaigh, C. M., O'Sullivan, G. J., Kinsella, A., Harvey, R. P., Tighe, O., Croke, D. T., et al. (2006). Sexually dimorphic changes in the exploratory and habituation profiles of heterozygous neuregulin-1 knockout mice. Neuroreport 17, 79–83. doi: 10.1097/01.wnr.0000192738.31029.0a
Paoletti, P., Bellone, C., and Zhou, Q. (2013). NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat. Rev. Neurosci. 14, 383–400. doi: 10.1038/nrn3504
Pappas, B. A., Gallivan, J. V., Dugas, T., Saari, M., and Ings, R. (1980). Intraventricular 6-hydroxydopamine in the newborn rat and locomotor responses to drugs in infancy: no support for the dopamine depletion model of minimal brain dysfunction. Psychopharmacology 70, 41–46. doi: 10.1007/BF00432368
Pei, J. C., Liu, C. M., and Lai, W. S. (2014). Distinct phenotypes of new transmembrane-domain neuregulin 1 mutant mice and the rescue effects of valproate on the observed schizophrenia-related cognitive deficits. Front. Behav. Neurosci. 8:126. doi: 10.3389/fnbeh.2014.00126
Pozzi, L., Baviera, M., Sacchetti, G., Calcagno, E., Balducci, C., Invernizzi, R. W., et al. (2011). Attention deficit induced by blockade of N-methyl D-aspartate receptors in the prefrontal cortex is associated with enhanced glutamate release and cAMP response element binding protein phosphorylation: role of metabotropic glutamate receptors 2/3. Neuroscience 176, 336–348. doi: 10.1016/j.neuroscience.2010.11.060
Price, R. B., Shungu, D. C., Mao, X., Nestadt, P., Kelly, C., Collins, K. A., et al. (2009). Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol. Psychiatry 65, 792–800. doi: 10.1016/j.biopsych.2008.10.025
Procaccini, C., Maksimovic, M., Aitta-Aho, T., Korpi, E. R., and Linden, A. M. (2013). Reversal of novelty-induced hyperlocomotion and hippocampal c-Fos expression in GluA1 knockout male mice by the mGluR2/3 agonist LY354740. Neuroscience 250, 189–200. doi: 10.1016/j.neuroscience.2013.07.010
Reisberg, B., Doody, R., Stoffler, A., Schmitt, F., Ferris, S., Mobius, H. J., et al. (2003). Memantine in moderate-to-severe Alzheimer's disease. N. Engl. J. Med. 348, 1333–1341. doi: 10.1056/NEJMoa013128
Row, B. W., Kheirandish, L., Neville, J. J., and Gozal, D. (2002). Impaired spatial learning and hyperactivity in developing rats exposed to intermittent hypoxia. Pediatr. Res. 52, 449–453. doi: 10.1203/00006450-200209000-00024
Sailasuta, N., Ernst, T., and Chang, L. (2008). Regional variations and the effects of age and gender on glutamate concentrations in the human brain. Magn. Reson. Imaging 26, 667–675. doi: 10.1016/j.mri.2007.06.007
Sakata, M., Toyohara, J., Ishibashi, K., Wagatsuma, K., Ishii, K., Zhang, M. R., et al. (2017). Age and gender effects of (11)C-ITMM binding to metabotropic glutamate receptor type 1 in healthy human participants. Neurobiol. Aging 55, 72–77. doi: 10.1016/j.neurobiolaging.2017.03.022
Sanz-Clemente, A., Nicoll, R. A., and Roche, K. W. (2013). Diversity in NMDA receptor composition: many regulators, many consequences. Neuroscientist 19, 62–75. doi: 10.1177/1073858411435129
Schaafsma, S. M., Gagnidze, K., Reyes, A., Norstedt, N., Mansson, K., Francis, K., et al. (2017). Sex-specific gene-environment interactions underlying ASD-like behaviors. Proc. Natl. Acad. Sci. U.S.A. 114, 1383–1388. doi: 10.1073/pnas.1619312114
Scholtzova, H., Wadghiri, Y. Z., Douadi, M., Sigurdsson, E. M., Li, Y. S., Quartermain, D., et al. (2008). Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging. J. Neurosci. Res. 86, 2784–2791. doi: 10.1002/jnr.21713
Scott-Van Zeeland, A. A., Dapretto, M., Ghahremani, D. G., Poldrack, R. A., and Bookheimer, S. Y. (2010). Reward processing in autism. Autism Res. 3, 53–67. doi: 10.1002/aur.122
Shaywitz, B. A., Gordon, J. W., Klopper, J. H., and Zelterman, D. A. (1977). The effect of 6-hydroxydopamine on habituation of activity in the developing rat pup. Pharmacol. Biochem. Behav. 6, 391–396. doi: 10.1016/0091-3057(77)90175-7
Shaywitz, B. A., Yager, R. D., and Klopper, J. H. (1976). Selective brain dopamine depletion in developing rats: an experimental model of minimal brain dysfunction. Science 191, 305–308. doi: 10.1126/science.942800
Sheikh-Bahaei, N., Sajjadi, S. A., Manavaki, R., McLean, M., O'Brien, J. T., and Gillard, J. H. (2018). Positron emission tomography-guided magnetic resonance spectroscopy in Alzheimer disease. Ann. Neurol. 83, 771–778. doi: 10.1002/ana.25202
Shimmura, C., Suda, S., Tsuchiya, K. J., Hashimoto, K., Ohno, K., Matsuzaki, H., et al. (2011). Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS ONE 6:e25340. doi: 10.1371/journal.pone.0025340
Shors, T. J., Falduto, J., and Leuner, B. (2004). The opposite effects of stress on dendritic spines in male vs. female rats are NMDA receptor-dependent. Eur. J. Neurosci. 19, 145–150. doi: 10.1046/j.1460-9568.2003.03065.x
Shulman, Y., Grant, S., Seres, P., Hanstock, C., Baker, G., and Tibbo, P. (2006). The relation between peripheral and central glutamate and glutamine in healthy male volunteers. J. Psychiatry Neurosci. 31, 406–410.
Smejkalova, T., and Woolley, C. S. (2010). Estradiol acutely potentiates hippocampal excitatory synaptic transmission through a presynaptic mechanism. J. Neurosci. 30, 16137–16148. doi: 10.1523/JNEUROSCI.4161-10.2010
Smith, S. E., Zhou, Y. D., Zhang, G., Jin, Z., Stoppel, D. C., and Anderson, M. P. (2011). Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci. Transl. Med. 3:103ra197. doi: 10.1126/scitranslmed.3002627
Sokolow, S., Luu, S. H., Nandy, K., Miller, C. A., Vinters, H. V., Poon, W. W., et al. (2012). Preferential accumulation of amyloid-beta in presynaptic glutamatergic terminals (VGluT1 and VGluT2) in Alzheimer's disease cortex. Neurobiol. Dis. 45, 381–387. doi: 10.1016/j.nbd.2011.08.027
Stefani, M. R., and Moghaddam, B. (2005). Transient N-methyl-D-aspartate receptor blockade in early development causes lasting cognitive deficits relevant to schizophrenia. Biol. Psychiatry 57, 433–436. doi: 10.1016/j.biopsych.2004.11.031
Stefansson, H., Sarginson, J., Kong, A., Yates, P., Steinthorsdottir, V., Gudfinnsson, E., et al. (2003). Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. Am. J. Hum. Genet. 72, 83–87. doi: 10.1086/345442
Stefansson, H., Sigurdsson, E., Steinthorsdottir, V., Bjornsdottir, S., Sigmundsson, T., Ghosh, S., et al. (2002). Neuregulin 1 and susceptibility to schizophrenia. Am. J. Hum. Genet. 71, 877–892. doi: 10.1086/342734
Stefansson, H., Steinthorsdottir, V., Thorgeirsson, T. E., Gulcher, J. R., and Stefansson, K. (2004). Neuregulin 1 and schizophrenia. Ann. Med. 36, 62–71. doi: 10.1080/07853890310017585
Sterley, T. L., Howells, F. M., Dimatelis, J. J., and Russell, V. A. (2016). Genetic predisposition and early life experience interact to determine glutamate transporter (GLT1) and solute carrier family 12 member 5 (KCC2) levels in rat hippocampus. Metab. Brain Dis. 31, 169–182. doi: 10.1007/s11011-015-9742-5
Stover, J. F., and Kempski, O. S. (2005). Anesthesia increases circulating glutamate in neurosurgical patients. Acta Neurochir. 147, 847–853. doi: 10.1007/s00701-005-0562-y
Swerdlow, N. R., and Geyer, M. A. (1998). Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr. Bull. 24, 285–301. doi: 10.1093/oxfordjournals.schbul.a033326
Tayoshi, S., Sumitani, S., Taniguchi, K., Shibuya-Tayoshi, S., Numata, S., Iga, J., et al. (2009). Metabolite changes and gender differences in schizophrenia using 3-Tesla proton magnetic resonance spectroscopy (1H-MRS). Schizophr. Res. 108, 69–77. doi: 10.1016/j.schres.2008.11.014
Tebartz van Elst, L., Maier, S., Fangmeier, T., Endres, D., Mueller, G. T., Nickel, K., et al. (2014). Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: evidence in support of the excitatory/inhibitory imbalance hypothesis. Mol. Psychiatry 19, 1314–1325. doi: 10.1038/mp.2014.62
Teichberg, V. I., Cohen-Kashi-Malina, K., Cooper, I., and Zlotnik, A. (2009). Homeostasis of glutamate in brain fluids: an accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience 158, 301–308. doi: 10.1016/j.neuroscience.2008.02.075
Tordera, R. M., Garcia-Garcia, A. L., Elizalde, N., Segura, V., Aso, E., Venzala, E., et al. (2011). Chronic stress and impaired glutamate function elicit a depressive-like phenotype and common changes in gene expression in the mouse frontal cortex. Eur. Neuropsychopharmacol. 21, 23–32. doi: 10.1016/j.euroneuro.2010.06.016
Tsai, G., and Coyle, J. T. (2002). Glutamatergic mechanisms in schizophrenia. Annu. Rev. Pharmacol. Toxicol. 42, 165–179. doi: 10.1146/annurev.pharmtox.42.082701.160735
Turic, D., Langley, K., Mills, S., Stephens, M., Lawson, D., Govan, C., et al. (2004). Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD. Mol. Psychiatry 9, 169–173. doi: 10.1038/sj.mp.4001387
Turic, D., Langley, K., Williams, H., Norton, N., Williams, N. M., Moskvina, V., et al. (2005). A family based study implicates solute carrier family 1-member 3 (SLC1A3) gene in attention-deficit/hyperactivity disorder. Biol. Psychiatry 57, 1461–1466. doi: 10.1016/j.biopsych.2005.03.025
Uezato, A., Kimura-Sato, J., Yamamoto, N., Iijima, Y., Kunugi, H., and Nishikawa, T. (2012). Further evidence for a male-selective genetic association of synapse-associated protein 97 (SAP97) gene with schizophrenia. Behav. Brain Funct. 8:2. doi: 10.1186/1744-9081-8-2
van den Buuse, M., Low, J. K., Kwek, P., Martin, S., and Gogos, A. (2017). Selective enhancement of NMDA receptor-mediated locomotor hyperactivity by male sex hormones in mice. Psychopharmacology 234, 2727–2735. doi: 10.1007/s00213-017-4668-8
Wang, Y., Ma, Y., Hu, J., Cheng, W., Jiang, H., Zhang, X., et al. (2015). Prenatal chronic mild stress induces depression-like behavior and sex-specific changes in regional glutamate receptor expression patterns in adult rats. Neuroscience 301, 363–374. doi: 10.1016/j.neuroscience.2015.06.008
Wei, J., Yuen, E. Y., Liu, W., Li, X., Zhong, P., Karatsoreos, I. N., et al. (2014). Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition. Mol. Psychiatry 19, 588–598. doi: 10.1038/mp.2013.83
Weiss, L. A., Shen, Y., Korn, J. M., Arking, D. E., Miller, D. T., Fossdal, R., et al. (2008). Association between microdeletion and microduplication at 16p11.2 and autism. N. Engl. J. Med. 358, 667–675. doi: 10.1056/NEJMoa075974
Winblad, B., Jones, R. W., Wirth, Y., Stoffler, A., and Mobius, H. J. (2007). Memantine in moderate to severe Alzheimer's disease: a meta-analysis of randomised clinical trials. Dement. Geriatr. Cogn. Disord. 24, 20–27. doi: 10.1159/000102568
Won, H., Lee, H. R., Gee, H. Y., Mah, W., Kim, J. I., Lee, J., et al. (2012). Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265. doi: 10.1038/nature11208
Woolley, C. S., Gould, E., Frankfurt, M., and McEwen, B. S. (1990). Naturally occurring fluctuation in dendritic spine density on adult hippocampal pyramidal neurons. J. Neurosci. 10, 4035–4039. doi: 10.1523/JNEUROSCI.10-12-04035.1990
Wozniak, D. F., Dikranian, K., Ishimaru, M. J., Nardi, A., Corso, T. D., Tenkova, T., et al. (1998). Disseminated corticolimbic neuronal degeneration induced in rat brain by MK-801: potential relevance to Alzheimer's disease. Neurobiol. Dis. 5, 305–322. doi: 10.1006/nbdi.1998.0206
Wyllie, D. J., Livesey, M. R., and Hardingham, G. E. (2013). Influence of GluN2 subunit identity on NMDA receptor function. Neuropharmacology 74, 4–17. doi: 10.1016/j.neuropharm.2013.01.016
Yang, M., Bozdagi, O., Scattoni, M. L., Wohr, M., Roullet, F. I., Katz, A. M., et al. (2012). Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice. J. Neurosci. 32, 6525–6541. doi: 10.1523/JNEUROSCI.6107-11.2012
Zahr, N. M., Mayer, D., Rohlfing, T., Chanraud, S., Gu, M., Sullivan, E. V., et al. (2013). In vivo glutamate measured with magnetic resonance spectroscopy: behavioral correlates in aging. Neurobiol. Aging 34, 1265–1276. doi: 10.1016/j.neurobiolaging.2012.09.014
Zhang, J., Li, Y., Xu, J., and Yang, Z. (2014). The role of N-methyl-D-aspartate receptor in Alzheimer's disease. J. Neurol. Sci. 339, 123–129. doi: 10.1016/j.jns.2014.01.041
Zhang, N., Zhong, P., Shin, S. M., Metallo, J., Danielson, E., Olsen, C. M., et al. (2015). S-SCAM, a rare copy number variation gene, induces schizophrenia-related endophenotypes in transgenic mouse model. J. Neurosci. 35, 1892–1904. doi: 10.1523/JNEUROSCI.3658-14.2015
Zhang, X., Li, Q., Wong, N., Zhang, M., Wang, W., Bu, B., et al. (2015). Behaviour and prefrontal protein differences in C57BL/6N and 129 X1/SvJ mice. Brain Res. Bull. 116, 16–24. doi: 10.1016/j.brainresbull.2015.05.003
Keywords: sex differences, glutamate, ADHD, Alzheimer's disease, schizophrenia, autism spectrum disorders (ASD), depression
Citation: Wickens MM, Bangasser DA and Briand LA (2018) Sex Differences in Psychiatric Disease: A Focus on the Glutamate System. Front. Mol. Neurosci. 11:197. doi: 10.3389/fnmol.2018.00197
Received: 27 March 2018; Accepted: 18 May 2018;
Published: 05 June 2018.
Edited by:
Jordan Marrocco, Rockefeller University, United StatesReviewed by:
Christina Dalla, National and Kapodistrian University of Athens, GreeceMaarten Van Den Buuse, La Trobe University, Australia
Copyright © 2018 Wickens, Bangasser and Briand. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lisa A. Briand, lbriand@temple.edu