Plasticity of Inhibitory Cells in Health and Disease

Editorial

10 January 2023

Editorial: Plasticity of inhibitory cells in health and disease

María Clara Gravielle

Leonardo Pignataro

and

Florence P. Varodayan

2,593 views

0 citations

Editors

Leonardo Pignataro

The City University of New York

Maria Clara Gravielle

University of Buenos Aires

Florence P. Varodayan

Binghamton University - SUNY

Impact

Motifs of local inhibition in the central nervous system. Generalized motifs of cortical inhibition are depicted that include cellular/subcellular targets and approximated effects on an excitatory postsynaptic potential (EPSP) recorded from a nearby pyramidal cell. To some extent, these inhibitory transmission motifs are present across all cortical layers, but some motifs are more prevalent in some layers based on where IN subtypes reside. (A) Feedback inhibition. A local inhibitory neuron (IN; circle) receives an excitatory transmission from long-range glutamate inputs or local competing ensembles or cortical columns (black arrows). Feedback INs regulate dendritic compartments of principal neurons (triangle) to decrease the amplitude of EPSPs. Cortical somatostatin (SST) INs represent a primary example of feedback INs. (B) Feedforward inhibition. A local IN and neighboring principal neuron receive coincidental excitatory input. Feedforward INs, often expressing parvalbumin (PV), are optimized to inhibit the nearby cell bodies rapidly and faithfully after receiving excitatory inputs. Through this process, feedforward INs restrict the window during which EPSPs may be converted into action potential firing. Feedforward INs can regulate dozens of related principal cells to recruit neuronal ensembles and generate oscillatory activity in many brain areas. (C) Disinhibition. INs can inhibit other INs to relieve inhibition and ultimately facilitate EPSPs on the principal neurons. Prime examples of this motif include SST-INs inhibiting PV-INs and vasoactive intestinal peptide (VIP) INs inhibiting SST-INs. (D) Blanket inhibition. Some INs subtypes help drive their activity to maintain wide networks of inhibition and low levels of excitatory drive throughout broad brain areas. For example, PV-INs form extensive gap junctions with other PV-INs and cholecystokinin INs can co-release glutamate to excite onto each other.

Review

29 August 2022

Targeting prefrontal cortex GABAergic microcircuits for the treatment of alcohol use disorder

Kenneth N. Fish

and

Max E. Joffe

Developing novel treatments for alcohol use disorders (AUDs) is of paramount importance for improving patient outcomes and alleviating the suffering related to the disease. A better understanding of the molecular and neurocircuit mechanisms through which alcohol alters brain function will be instrumental in the rational development of new efficacious treatments. Clinical studies have consistently associated the prefrontal cortex (PFC) function with symptoms of AUDs. Population-level analyses have linked the PFC structure and function with heavy drinking and/or AUD diagnosis. Thus, targeting specific PFC cell types and neural circuits holds promise for the development of new treatments. Here, we overview the tremendous diversity in the form and function of inhibitory neuron subtypes within PFC and describe their therapeutic potential. We then summarize AUD population genetics studies, clinical neurophysiology findings, and translational neuroscience discoveries. This study collectively suggests that changes in fast transmission through PFC inhibitory microcircuits are a central component of the neurobiological effects of ethanol and the core symptoms of AUDs. Finally, we submit that there is a significant and timely need to examine sex as a biological variable and human postmortem brain tissue to maximize the efforts in translating findings to new clinical treatments.

7,164 views

19 citations

Proposed CeA neurocircuit model and summary alcohol effects on CeA neurotransmission. In alcohol-naive circuitry, the CeAL receives glutamatergic input from various brain regions and sends GABAergic projections to the CeAM. The CeAM, which also receives some direct input from similar regions as the CeAL, in turn sends GABAergic projections to various brain regions. Acute application of EtOH to CeA slices increases glutamatergic neurotransmission in the CeAL, an effect regulated by astrocytic function. We propose the increased glutamatergic release acts on CeAL neurons leading to an increase in GABA release in the CeAM. After chronic alcohol exposure, in addition to astrocytic function, microglia may also play a role in the increase in glutamatergic transmission through upregulation of activated microglial activity. BLA, basolateral amygdala; VTA, ventral tegmental area; LC, locus coeruleus; BNST, bed nucleus of the stria terminalis; PVN, paraventricular nucleus; NTS, nucleus of the tractus solitarius. Created with BioRender.com.

Review

05 July 2022

Subregional Differences in Alcohol Modulation of Central Amygdala Neurocircuitry

Mariam Melkumyan

and

Yuval Silberman

3,263 views

5 citations

Mini Review

19 May 2022

The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms

Caitlyn A. Chapman

, 1 more and

Tija C. Jacob

Relative local calcium levels facilitate glutamatergic and GABAergic synaptic crosstalk and plasticity responses through an intersection of downstream signaling pathways. Left: Strong glutamatergic activation and high calcium influx (yellow) triggers excitatory long-term potentiation (eLTP) associated with ERK1/2-mediated insertion of synaptic AMPARs, which is facilitated by translocation of CaMKIIα to excitatory synapses and interaction with NMDARs. CaMKIIα phosphorylation additionally stabilizes synaptic AMPARs. eLTP also induces heterosynaptic long-term depression of nearby inhibitory synapses (iLTD). During iLTD, calcineurin-mediated dephosphorylation of γ2-GABAARs increases receptor mobility and diffusion to extrasynaptic sites, while ERK1/2-mediated gephyrin phosphorylation and calpain protease activity disassembles the gephyrin scaffold. Right: During low-moderate NMDAR activation, CaMKIIα translocation to inhibitory synapses facilitates inhibitory long-term potentiation (iLTP) through synaptic gephyrin recruitment and enhanced β3-GABAAR forward trafficking and membrane insertion. Simultaneously, moderate NMDAR stimulation triggers a calcineurin-mediated reduction in surface AMPARs and calpain proteolytic degradation of NMDAR-GluN2B subunit and glutamatergic PSD95 scaffold (excitatory long-term depression, eLTD). eLTD and spine shrinkage is also observed in response to eLTP of proximal spines, while iLTP occurs at synapses distant from the potentiating spine. Bottom: Activation of group I metabotropic mGluR induces downstream IP3 receptor activation and release of calcium stores from the endoplasmic reticulum. The moderate increase in calcium concentration (pink) prompts PKC-mediated GABAAR phosphorylation and stabilization, contributing to the strengthening of inhibitory synapses during iLTP. Created with BioRender.com.

Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response to changes in activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones and their functional integration within dendritic regions, concurrent plasticity has historically been underassessed. Growing evidence for pathological disruptions in the excitation and inhibition (E/I) balance in neurological and neurodevelopmental disorders indicates the need for an improved, more “holistic” understanding of synaptic interplay. There continues to be a long-standing focus on the persistent strengthening of excitation (excitatory long-term potentiation; eLTP) and its role in learning and memory, although the importance of inhibitory long-term potentiation (iLTP) and depression (iLTD) has become increasingly apparent. Emerging evidence further points to a dynamic dialogue between excitatory and inhibitory synapses, but much remains to be understood regarding the mechanisms and extent of this exchange. In this mini-review, we explore the role calcium signaling and synaptic crosstalk play in regulating postsynaptic plasticity and neuronal excitability. We examine current knowledge on GABAergic and glutamatergic synapse responses to perturbances in activity, with a focus on postsynaptic plasticity induced by short-term pharmacological treatments which act to either enhance or reduce neuronal excitability via ionotropic receptor regulation in neuronal culture. To delve deeper into potential mechanisms of synaptic crosstalk, we discuss the influence of synaptic activity on key regulatory proteins, including kinases, phosphatases, and synaptic structural/scaffolding proteins. Finally, we briefly suggest avenues for future research to better understand the crosstalk between glutamatergic and GABAergic synapses.

13,297 views

39 citations