Overview:  Autism has long been thought to result from abnormal development of brain connections called synapses, but new research highlights the SHANK family as key synaptic players in this spectrum of disorders.

Background:  SHANK 1, 2, and 3 are “scaffolding proteins,” so called because they literally hold together synaptic components.  Many of these synaptic molecules include neurotransmitter receptors that bind to glutamate to produce an excitatory signal in the brain.  SHANK2 and SHANK3 identified as ASD risk genes in 2010 and 2007, respectively.

What's New:

1) Mutations of all SHANK family members have now been linked to Autism Spectrum Disorders (ASD).  The May 2012 issue of the American Journal of Human Genetics reported genetic evidence gathered from 1,158 Canadian and 456 European individuals with ASD, compared with >15,000 controls.  The researchers found two types of SHANK1 mutations associated with ASD in males but not females.

2) Mouse models of ASD were recently created by manipulating the SHANK2 gene.  Both models, published in Nature in June 2012, showed behaviors similar to core symptoms of ASD such as abnormal social interaction, reduced communication, and repetitive grooming or jumping.  These behaviors also correlated with weaker synaptic function of excitatory neurotransmitter receptors, presumably because their SHANK2 synaptic scaffolds are missing.

Why It’s Important:  Together, emerging evidence from SHANK-related research is paving the way for discovery of new targeted ASD drug treatments.  For example, to test for potential new ASD treatments, one of these research groups treated their ASD mouse model with drugs that activate excitatory neurotransmitter receptors.  They were able to restore normal social interaction by stimulating a type of excitatory neurotransmitter receptor called the NMDA receptor, either directly with D-cycloserine, or indirectly with an activator of another type of excitatory neurotransmitter receptor called the mGluR5 receptor.

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How Do Autism Risk Genes Affect Brain Function?

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