Several critical questions remain poorly understood to understand the pathophysiology of ASDs. The molecular and circuit-level mechanisms underlying autism behaviors are mostly unknown. Moreover, the developmental origin of autistic behaviors has not been delineated. Numerous challenges have been encountered in modeling autism mutations in mice. First, recent genetics studies have identified mutations in a long list of genes implicated in ASDs. However, most of these mutations are rare and private. The full spectrum of clinical features associated with these genetic defects is not known, posing a significant challenge for experimental design and potential to overly generalize findings from individual models. Second, the lack of robust and strong behavioral assays for measuring behaviors that resemble human ASDs remains a significant obstacle to dissect the circuit-level mechanisms. Third, various effects on synapses in different brain regions and different stages of development makes it difficult to establish a link between synaptic dysfunction and behavioral impairments. These challenges thus demand a shift from the current analytic paradigm that combines behavior, synaptic electrophysiology, and biochemical approaches. We propose that an analytic paradigm that integrates the
