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The Effects of Npas4 and Sema4D on Inhibitory Synapse Formation

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United States

During development, hundreds of proteins direct the formation and maintenance of synapses (connections between brain cells) that shape the proper circuitry of the brain. As synapses form, eliminate, and re-form, a precise balance between the inhibitory and excitatory synaptic inputs must be attained for accurate brain function. Mutations in the proteins that regulate synapse development give rise to defects in these processes and have been suggested to be responsible for disorders of human cognitive function such as Autism Spectrum Disorders (ASD). Dr. Greenberg and colleagues have identified an activity-regulated gene Npas4 that encodes a protein required specifically for the formation of inhibitory synapses. However, the molecular mechanism by which Npas4 selectively controls the formation of inhibitory synapses remains unknown. This project will use mice deficient in Npas4 to gain insight into this process. Genome-wide screens will also be carried out to identify the genetic program that Npas4 regulates to promote inhibitory synapse formation. Special attention will be given to those genes that map to regions implicated in ASD by human linkage and association studies as they will be considered ASD candidate genes. The researchers hope to gain insights into the experience-dependent molecular processes responsible for ASD, and ultimately uncover therapies and cures for this devastating disease. What this means to people with autism: To understand the causes of ASD and ultimately identify treatments and cures, it is important to understand the genetic and environmental cues that govern synapse development and create the proper balance between inhibition and excitation in the brain.