Rare penetrant mutations, common genetic variants and environmental factors are known to contribute risk to ASD, yet, about 80% of the cases have no clear etiology and no pathogenetic model. A large number of rare mutations have been identified in the context of syndromic and non-syndromic ASD and have been modeled in various organisms. However, these mutations are extremely heterogeneous, each accounting for less than 1–2% of cases. Furthermore, in no instance have they been shown to be sufficient to cause ASD; rather, they interact with other inherited and non-inherited risk factors. Some mutations involve synapse-associated molecules (Sudhof, 2008; Zoghbi and Bear, 2012) and have led to the widespread notion that alterations in the assembly of synaptic connections are key in the pathophysiology of ASD. Others have formulated the hypothesis that there is an excitatory/inhibitory neuron imbalance in the disorder (Casanova et al., 2003; Rubenstein, 2010).
