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.
Highlights
The term “autism” as a unique disease concept was first used by Leo Kanner in 1943
It is estimated that a genetic cause can be identified in up to 25% of Autism spectrum disorder (ASD) cases, chromosomal rearrangements and coding-sequence mutations making up ∼10–20% and ∼5–10% of ASD patients, respectively (Huguet et al, 2013; Ziats and Rennert, 2016)
It has been shown that knockout of Nlgn3 late in development produces a marked synaptic phenotype, but no detectable effects are seen after knockout during early development, apparently due to developmental compensation by cerebellin-1 (Clbn1), a secreted protein binding to Nrxn (Xing et al, 2018)
Summary
The term “autism” as a unique disease concept was first used by Leo Kanner in 1943. He described eight boys and three girls, aged two to eight, who were unable to use language to communicate, displaying monotonous repetitions and preoccupation with objects (Kanner, 1995). To carry a higher global burden of rare, large CNVs which can include known ASD associated synaptic genes, such as SHANK3 and CHD10 (Guo et al, 2017) These genes encode cell adhesion molecules, scaffolding proteins, and proteins involved in synaptic transcription, protein synthesis and degradation, which affect various aspects of synapses, including synapse formation and elimination, synaptic transmission and plasticity, suggesting that the pathogenesis of ASD, at least in part, may be attributed to synaptic dysfunction, which can lead to functional and cognitive impairments. It has been shown that knockout of Nlgn late in development produces a marked synaptic phenotype, but no detectable effects are seen after knockout during early development, apparently due to developmental compensation by cerebellin-1 (Clbn1), a secreted protein binding to Nrxn (Xing et al, 2018) This may explain why Nlgn KO mice have no phenotype in previous studies. Nlgn KO significantly decreases the peak amplitude and the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), without changing mIPSCs, sEPSCs and mEPSCs in CA3 pyramidal cells, confirming that Nlgn knockout affects primarily inhibitory transmission (Hammer et al, 2015)
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