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Background  The genetics of autism spectrum disorder (hereafter referred to as “autism”) are rapidly unfolding, with a significant increase in the identification of genes implicated in the disorder. Many of these genes are part of a complex landscape of genetic variants that are thought to act together to cause the behavioral phenotype associated with autism. One of the few single-locus causes of autism involves a mutation in the SH3 and multiple ankyrin repeat domains 3 ( SHANK3 ) gene. Previous electrophysiological studies in mice with  Shank3  mutations demonstrated impairment in synaptic long-term potentiation, suggesting a potential disruption at the synapse.    Methods  To understand how variants in  SHANK3  would lead to such impairments and manifest in the brain of patients with autism, we assessed the presence of synaptic pathology in  Shank3- deficient mice at 5 weeks and 3 months of age, focusing on the stratum radiatum of the CA1 field. This study analyzed both  Shank3  heterozygous and homozygous mice using an electron microscopy approach to determine whether there is a morphological correlate to the synaptic functional impairment.    Results  As both synaptic strength and plasticity are affected in  Shank3- deficient mice, we hypothesized that there would be a reduction in synapse density, postsynaptic density length, and perforated synapse density. No differences were found in most parameters assessed. However,  Shank3  heterozygotes had significantly higher numbers of perforated synapses at 5 weeks compared to 3 months of age and significantly higher numbers of perforated synapses compared to 5-week-old wildtype and  Shank3  homozygous mice.    Conclusions  Although this finding represents preliminary evidence for ultrastructural alterations, it suggests that while major structural changes seem to be compensated for in  Shank3- deficient mice, more subtle morphological alterations, affecting synaptic structure, may take place in an age-dependent manner.

Ultrastructural analyses in the hippocampus CA1 field in Shank3-deficient mice