Targeting Excitation-Inhibition Imbalance in Neurodevelopmental and Autism Spectrum Disorders

A tight balance between excitation and inhibition (E/I balance) in synaptic inputs to a neuron and in neural circuits is important for correct brain development and function. E/I imbalances have been implicated in numerous brain and neurodevelopmental disorders, such as Autism Spectrum Disorders (ASDs). ASDs refer to a wide range of neurodevelopmental disorders and a variety, a “spectrum” of symptoms, skills, and levels of disability. Some patients are mildly impaired by their symptoms, which primarily include social-communication deficits, repetitive behaviors and restricted interest, while others are severely disabled and show associated symptoms, including movement abnormalities, sensory issues, seizures, learning disabilities, developmental regression and gastrointestinal symptoms. Although most ASDs present without an apparent cause (i.e. idiopathic), “syndromic forms” are frequent and result from single-gene defects. They include disorders such as Tuberous Sclerosis Complex 1 and 2 (TSC 1 and 2), Fragile X syndrome (FXS), Angelman syndrome, Rett syndrome (RTT), and CDKL5 deficiency disorder (CDD). Several studies, both at cellular and circuit level, have hypothesized that some of these syndromic forms of ASD might be caused by an excitation/inhibition (E/I) imbalance.

Such imbalances are frequently observed in animal models harboring genetic modifications of ASD‐associated genes, and their pharmacological correction has the potential to normalize key autistic-like phenotypes in these animals. Although the hypothesis that E/I imbalance contributes to development and maintenance of ASDs has widely been accepted and some candidate mechanisms underlying E/I imbalances in animal models of ASDs have been identified, additional studies are needed to better understand the causal relationship between E/I imbalance and autistic-like phenotypes. Neuronal E/I balance is established and tightly regulated by several factors at synaptic or circuit levels. Specific factors that contribute to synaptic E/I balance include excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signaling pathways, homeostatic synaptic plasticity, and intrinsic neuronal excitability. At the circuit level, E/I balance involves local circuits such as the interplay between GABAergic interneurons and target pyramidal neurons, which modulate long-range connections. Although several studies point to a local hyperconnectivity and long-range hypoconnectivity and disconnection between neural circuits in ASD, the pathogenic mechanisms underlying E/I imbalance in ASDs might be more complex than expected. Indeed, recent studies have begun to show that the same gene mutation leads to distinct synaptic E/I imbalances in different synapses, cell types, and brain regions at different time points. These findings highlight the importance of pursuing detailed and integrative analyses of E/I imbalances in studies of animal models of ASD. Understanding the different cellular environments and finely regulated time-windows influencing E/I imbalance in ASDs brains is not only required to improve basic understanding of the causal link between E/I imbalance and the initiation, development and maintenance of autistic-like phenotypes, but has important implications for developing better pharmacological treatments, as it may lead to individuating specific therapeutic windows to address aberrant neuronal development in ASDs. Therefore, in this Research Topic we welcome innovative studies, as well as reviews on this fascinating aspect in Neurodevelopmental and Autism Spectrum Disorders.