Significant progress has been made recently towards understanding the molecular mechanisms that control synapse development in the mammalian brain. Our laboratory has uncovered a role for the activity-regulated bHLH transcription factor, Npas4, in the development of inhibitory synapses onto excitatory neurons and resulting effects on the balance between inhibitory and excitatory synapses. To understand the mechanism by which Npas4 controls inhibitory synapse development in vivo, we have generated mice that carry a cre-mediated conditional knockout mutation of f lpas4 Using this conditional knockout approach, we will examine the effect of loss of Npas4 on inhibitory synapse formation and function at various times during development. We will also use this mouse model to test the role of Npais4 on inhibitory synapse maturation and sensory experience-mediated synaptic plasticity in the developing visual cortex. In addition, we will use a combination of chromatin immunoprecipitation-sequencing and transcriptome-sequencing in conjunction with bioinformatics analysis to identify on a genome-wide scale the DNA occupancy sites of Npas4 and the RNA transcripts that Npas4 regulates. These studies will provide new insights into the genetic program that Npas4 controls to mediate its effect on inhibitory synapse development and the balance between excitatory and inhibitory inputs in the mammalian brain. These studies will be crucial to our understanding of how disorders of cognitive function such as autism spectrum disorders may arise when the delicate excitatory/inhibitory balance is disrupted and may suggest targets for treatments of these diseases.

Public Health Relevance

As defects in the balance between excitation and inhibition can lead to disorders of cognitive function such as autism spectrum disorders, understanding how this delicate balance is established and maintained is crucial for the discovery of therapies to treat or prevent these diseases of cognition.

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National Institute of Neurological Disorders and Stroke (NINDS)
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Dana-Farber Cancer Institute
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