Despite the diversity and the rising prevalence of diagnosed cases of autism, the etiology of the disorder remains an open question. Efforts to understand the pathophysiology of autism have focused on genetic factors. However, considering the tremendous diversity of autism types, it seems likely that the causes of autism spectrum disorders are numerous and perhaps overlapping.

Gord Fishell and his colleagues at New York University propose that the etiology of autism spectrum disorders can be best understood as an impairment of specific neuronal circuits, resulting from multiple genetic mutations.

Malfunction of interneurons in the cortex, brain cells that serve as brain-signaling gates, may cause some forms of autism. Research findings over the past five years support this hypothesis.

The Fishell laboratory and other groups have begun genome-wide analyses of the genes expressed by cortical interneurons. A number of genes associated with a variety of psychiatric disorders, including autism, are more strongly expressed in the developing interneurons of people with one of the disorders.

By contrast, pyramidal neurons, which directly process excitatory signaling, do not seem to show a similar enrichment. Studies have not yet explored in detail the role of these autism-associated genes for the proper functioning of inhibitory brain circuits. Fishell and his team plan to explore the genes involved in the functioning of a subtype of inhibitory interneurons called fast-spiking cortical basket cells.

Using a combination of approaches, including mouse genetics, electrophysiology, genomics and behavioral investigations, the researchers aim to examine how the loss of function of the genes MEF2C and RBFOX1 affects the development of basket cells and synaptic function in the cerebral cortex. This work may lead to mechanistic insights into how the malfunction of one crucial type of cortical interneuron can disrupt cortical circuits and result in autism symptoms.