Involvement of synaptic genes in the pathogenesis of autism spectrum disorders: the case of synapsins

Abstract

Autism spectrum disorders (ASDs) are heterogeneous neurodevelopmental disorders characterized by deficits in social interaction and social communication, restricted interests, and repetitive behaviors. Many synaptic protein genes are linked to the pathogenesis of ASDs, making them prototypical synaptopathies. An array of mutations in the synapsin (Syn) genes in humans has been recently associated with ASD and epilepsy, diseases that display a frequent comorbidity. Syns are pre-synaptic proteins regulating synaptic vesicle traffic, neurotransmitter release, and short-term synaptic plasticity. In doing so, Syn isoforms control the tone of activity of neural circuits and the balance between excitation and inhibition. As ASD pathogenesis is believed to result from dysfunctions in the balance between excitatory and inhibitory transmissions in neocortical areas, Syns are novel ASD candidate genes. Accordingly, deletion of single Syn genes in mice, in addition to epilepsy, causes core symptoms of ASD by affecting social behavior, social communication, and repetitive behaviors. Thus, Syn knockout mice represent a good experimental model to define synaptic alterations involved in the pathogenesis of ASD and epilepsy.

Keywords: autism; human mutations; knockout mice; social behavior; synaptic transmission; synaptic vesicles; synaptopathies.

Figure 1

Schematic diagram illustrating pre- and post-synaptic gene products implicated in ASD. Glutamate (GLU) and GABA synapses are shown. Different colors code for synaptic function: yellow, synaptic vesicle cycling; green, synapse formation and maintenance; red, neuronal excitability and neurotransmission; violet, glutamate receptors (GluR) signaling/trafficking.

Figure 2

Summary of the abnormalities in social behavior (gray squares) observed in young (Y, 2-month old) and adult (A, 6-month old) Syn I, Syn II, and Syn III KO mice with respect to the behavior of age-matched controls sharing the same genetic background [data from Ref. (65)]. Adults, but not young, Syn I and Syn II KO mice are epileptic.

Figure 3

Human mutations in SYN1 and SYN2 associated with epilepsy and/or ASD. Nonsense and missense mutations are indicated in blue and black, respectively together with the associated pathology (E, epilepsy; ASD, autism spectrum disorder).