Common Ribs of Inhibitory Synaptic Dysfunction in the Umbrella of Neurodevelopmental Disorders

Abstract

The term neurodevelopmental disorder (NDD) is an umbrella term used to group together a heterogeneous class of disorders characterized by disruption in cognition, emotion, and behavior, early in the developmental timescale. These disorders are heterogeneous, yet they share common behavioral symptomatology as well as overlapping genetic contributors, including proteins involved in the formation, specialization, and function of synaptic connections. Advances may arise from bridging the current knowledge on synapse related factors indicated from both human studies in NDD populations, and in animal models. Mounting evidence has shown a link to inhibitory synapse formation, specialization, and function among Autism, Angelman, Rett and Dravet syndromes. Inhibitory signaling is diverse, with numerous subtypes of inhibitory interneurons, phasic and tonic modes of inhibition, and the molecular and subcellular diversity of GABAA receptors. We discuss common ribs of inhibitory synapse dysfunction in the umbrella of NDD, highlighting alterations in the developmental switch to inhibitory GABA, dysregulation of neuronal activity patterns by parvalbumin-positive interneurons, and impaired tonic inhibition. Increasing our basic understanding of inhibitory synapses, and their role in NDDs is likely to produce significant therapeutic advances in behavioral symptom alleviation for interrelated NDDs.

CHIMERA repetitive mild traumatic brain injury induces chronic behavioural and neuropathological phenotypes in wild-type and APP/PS1 mice

“…PTSD is also associated with psychogenic non-epileptic seizures in veterans [81]. Because seizure activity is associated with altered GABAergic signalling [2], APP/PS1 mice develop age-dependent changes in synaptic dysfunction and altered GABAergic neurotransmission [71], and the A5-GABAα receptor has been identified in mice to modify fear extinction [28], it is possible that rmTBI may affect how Aβ interacts with GABAergic neurotransmission. Another possibility is sleep disruption, which occurs both in AD [86] and after TBI [64] and may influence both neuroinflammation and behaviour [22].…”

Molecular Specialization of GABAergic Synapses on the Soma and Axon in Cortical and Hippocampal Circuit Function and Dysfunction

“…The coordination of excitatory principal cell firing relies on interneuron function, and dysregulation of soma and axon targeting interneurons has been identified in disorders of the nervous system (DeFelipe et al, 1993; Rubenstein and Merzenich, 2003; Ali Rodriguez et al, 2018). Disruption of neuronal DG directly impacts the maintenance of CCK positive basket terminals onto pyramidal cell somas, leading to impaired CCK positive interneuron mediated neurotransmission and functional connectivity.…”

“…Disruption in inhibitory signaling mediated by PV positive cells on a global level has been associated with neurodevelopmental disorders (Ali Rodriguez et al, 2018). Schizophrenia, through post-mortem studies and in animal models, has been associated with soma and axon targeting inhibitory synapses (Lewis et al, 2008, 2012; Hines et al, 2013).…”

“…Schizophrenia, through post-mortem studies and in animal models, has been associated with soma and axon targeting inhibitory synapses (Lewis et al, 2008, 2012; Hines et al, 2013). Autism spectrum and related disorders such as Angelman syndrome and Rett syndrome have also been linked to PV cell dysfunction, and notably these disorders have a high incidence of epilepsy (Table 1; Kalscheuer et al, 2009; Shimojima et al, 2011; Ali Rodriguez et al, 2018). Mutations in the GABA A R subunit genes have been implicated in genetic epilepsies (Baulac et al, 2001; Wallace et al, 2001; Hines et al, 2018).…”

Targeting GABAAR-Associated Proteins: New Modulators, Labels and Concepts

“…γ-aminobutyric acid type A receptors (GABA A Rs) are the principal mediators of phasic and tonic inhibition in the human brain, being a vital part of the molecular machinery that creates cognition, behavior, and consciousness (Fritschy and Panzanelli, 2014). Dysfunctional GABA A Rs are involved in the pathogenesis of neurodevelopmental disorders (Ali Rodriguez et al, 2018), schizophrenia (de Jonge et al, 2017), postpartum depression (Mody, 2019), epilepsy (Palma et al, 2017; Hines et al, 2018), Alzheimer’s disease (Govindpani et al, 2017), autism (Vien et al, 2015) and stroke (Darmani et al, 2016; Wang et al, 2018). Structurally, these receptors belong to the pentameric ligand-gated ion channels harboring an extracellular domain (ECD), followed by four helical transmembrane domains (TMDs) and loops connecting these helices.…”