Synaptopathology Involved in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) encompasses a group of multifactorial neurodevelopmental disorders characterized by impaired social communication, social interaction and repetitive behaviors. ASD affects 1 in 59 children, and is about 4 times more common among boys than among girls. Strong genetic components, together with environmental factors in the early stage of development, contribute to the pathogenesis of ASD. Multiple studies have revealed that mutations in genes like NRXN, NLGN, SHANK, TSC1/2, FMR1, and MECP2 converge on common cellular pathways that intersect at synapses. These genes encode cell adhesion molecules, scaffolding proteins and proteins involved in synaptic transcription, protein synthesis and degradation, affecting various aspects of synapses including synapse formation and elimination, synaptic transmission and plasticity. This suggests that the pathogenesis of ASD may, at least in part, be attributed to synaptic dysfunction. In this article, we will review major genes and signaling pathways implicated in synaptic abnormalities underlying ASD, and discuss molecular, cellular and functional studies of ASD experimental models.

Behavioural and brain ultrastructural changes following the systemic administration of propionic acid in adolescent male rats. Further development of a rodent model of autism

“…Our study revealed relatively high susceptibility of the CA1 hippocampal area to PPA treatment. Molecular, histological and biochemical data also point out the altered CA1 area in PPA and other autism models (Dahlhaus et al, 2010;Guang et al, 2018;MacFabe et al, 2007). The special vulnerability of this region to various neuropathological conditions (epilepsy, depression, encephalitis, stroke, limbic encephalitis, hypoglycaemic encephalopathy, multiple sclerosis, transient global amnesia, Alzheimer disease, etc.)…”

“…Autism spectrum disorders (ASDs) are highly heritable, complex and pervasive conditions, characterized by communication deficits, restricted interests, emotional problems and cognitive impairments. Many genes traditionally thought to be involved in autism encode cell adhesion molecules and proteins involved in neurogenesis, synaptogenesis, synaptic functions and other cellular processes (Chen, Chang, & Huang, ; Guang et al, ; Zhao et al, ). In addition to the genetic component, a number of environmental factors participate in autism pathogenesis, affecting synapse activities, neuroimmune regulation, gastrointestinal function, metabolism and gene expression (Choi et al, ; Huang & Jin, ; MacFabe, ; Rizzetto, Fava, Tuohy, & Selmi, ).…”

“…Therefore, it is not clear how PPA-mediated effects are translated into specific ultrastructural elements of the brain. Traditionally ASD is considered a disorder of synaptic dysfunction and cell signalling with neuroinflammatory and neurometabolic components (Dipasquale et al, 2017;Guang et al, 2018;Pardo & Meffert, 2018;Siniscalco, Schultz, Brigida, & Antonucci, 2018). Therefore, the elucidation of the fine structure of synapses, other forms of cell signalling, mitochondria and possible metabolic alterations in the PPA-treated brain should be of special importance.…”

Cell-type-specific synaptic imbalance and disrupted homeostatic plasticity in cortical circuits of ASD-associatedChd8haploinsufficient mice

“…E:I balance governs the output of neurons based on the local level of excitatory/inhibitory synaptic transmission and intrinsic excitability. Some of the highest confidence ASD-risk genes encode proteins that directly impact E:I balance (4,5) and multiple animal models display synaptic transmission deficits alongside ASD-like behavioral abnormalities (2,(6)(7)(8)(9)(10)(11)(12). E:I balance is sustained through homeostatic plasticity mechanisms that maintain network activity within an optimal range by tuning synaptic strength (13) and intrinsic excitability (14).…”

Machine learning analysis of exome trios to contrast the genomic architecture of autism and schizophrenia

“…There is evidence that changes in calcium signaling may be associated with ASD [43][44][45]. Similarly, multiple studies support a link of immune dysfunction and inflammation to ASD [46][47][48], while strong evidence exists for a link with synaptic structures [49][50][51][52]. Upregulation of immune genes and downregulation of synaptic genes was observed in the postmortem brains of idiopathic ASD patients [53,54].…”