The goal of this collaboration is to identify targets for therapeutic intervention in autism spectrum disorders. Autism spectrum disorders are neurodevelopmental disorders characterized by deficits in social interaction, communication, and unusual repetitive behaviors [1, 2]. Autistic individuals can understand isolated facts but can not process complex information. Most recent estimates suggest that 1 in 166 children are affected by disorders of the autism spectrum. This high incidence and substantial societal cost make identifying treatment strategies for autism a high priority. However, the fundamental cellular and physiological alterations underlying autism-spectrum disorders are not understood.

Autism-spectrum disorders are amongst the most heritable neurodevelopmental disorders known to date. Human genetic studies conducted over the past 5-10 years have led to the identification of several candidate genes that may confer susceptibility to autism but also environmental risk factors might exist.  Each of these genetic and environmental risk factors appears to account for only a small fraction of autism cases. This apparent heterogeneity in the etiology of autism poses a major problem for therapeutic intervention and makes it mandatory to identify unifying alterations in the nervous system that represent the fundamental basis of autism pathology.

From recent work, synaptic connectivity and synapse function in the central nervous system have emerged as key targets for autism [3, 4]. Several of the autism-associated genetic defects identified to date occur in synaptic proteins and it is believed that synaptic dysfunction underlies the manifestation of behavioral and cognitive alterations. In particular, mutations and copy number variations in genes encoding a synaptic adhesion complex called the neuroligin-neurexin complex have been identified and verified in multiple independent studies [5-9]. Mouse models recapitulating these mutations exhibit defects in synaptic physiology and animal behavior, thereby further supporting an important role for these mutations in the etiology of autism [10-12]. However, the fundamental cellular and molecular changes caused by these mutations are not understood. Moreover, it is not known whether there is a common synaptic core pathway that is perturbed in multiple different models of autism. For example, it is conceivable that mutations in transcriptional and translational regulators (such as MeCP2 and FMR1, see below) or environmental insults (such as valproate exposure, see below) converge in the perturbation of synaptic signaling processes, revealing a unifying substrate underlying the etiology of autism.