Cover Story 2014, Volume 9 Issue 2
Autism spectrum disorders (ASDs) are neurologic disorders of developmental origin that share a complex and heterogeneous etiology. ASDs are characterized by profound deficits in social interaction, communication skills, and repetitive and stereotypic behaviors. The prevalence of ASD has increased to >1% of U.S. children over the past a few decades, underscoring the urgent need for both a better mechanistic understanding of its etiology, and the development of more effective therapies. Research spanning multiple disciplines, including genetics, genomics, brain connectivity, and behavior, has improved our understanding of ASDs, yet there is much more to learn. Heritability and heterogeneity are two major hallmarks of ASD. Autism has one of the strongest genetic components of all major neuropsychiatric disorders although no single genetic condition accounts for more than a small fraction of ASD cases. Current models of ASD pathogenesis posit that the interplay between a multitude of genetic and environmental mechanisms during the protracted process of neurodevelopment alters the normal trajectory of brain ontology. The discovery of the single-gene causes of syndromic forms of ASD has greatly informed our understanding of the molecular pathways disrupted at the neuronal synapse. The highly penetrant mutations of these single genes associated with synaptic structure and function substantiate the view of ASDs as childhood disorders of the neuronal misconnectivity. In a review in this issue, McGee et al. summarizes several prominent autism risk genes that contribute to the normal establishment and function of excitatory synapses. The illustration on the cover provides an over-simplified depiction of signal transduction at an excitatory central synapse. A cultured hippocampal neuron is labeled by immunocytochemistry to reveal a presynaptic protein (synapsin I, green), a postsynaptic protein (PSD-95, red), and locations of potential excitatory synapses as the apposition of these markers(overlapped pixels, yellow). The synaptic proteins implicated in ASD are labeled in bold font, and their molecular and signaling context are depicted in the overlay cartoon illustrating macromolecular assemblies of both pre- and post-synaptic structures (Image illustration by Shenfeng Qiu. See pages 137-150 by McGee et al. for more information).[Detail] ...