Abstract. This proposal aims to investigate the molecular basis of structural plasticity of inhibitory GABAergic interneurons (INs) in the mammalian forebrain. Cortical and hippocampal INs play critical roles in perception and memory storage; their abnormalities have been associated with a broad spectrum of neurological disorders in humans. It is well-established that INs undergo morphological changes and reorganize their networks after sensory experience. This phenomenon appears to be equally important for assembly of synaptic connectivity during development and for processing of information in the brain across lifespan, but the underlying molecular mechanisms are poorly understood. By using unbiased screening and mouse genetics, we have identified transcription factors (TFs) that regulate the architectures of IN networks in the hippocampus. Our preliminary studies support the hypothesis that these TFs are essential for appropriate GABAergic inhibition of pyramidal neurons and memory storage. We will use innovative approaches to elucidate the role of transcription in inhibitory circuits in unique mouse models. Our specific aims are: 1) To test how ablation of TFs in genetically defined IN subtypes impacts their morphologies, wiring and physiology; 2) To examine the consequences of TF signaling on sensory processing and memory formation; and 3) To identify TF effector genes. Taken together, these studies will provide new and significant insights into thus far poorly understood molecular mechanisms of IN plasticity.

Abnormalities in neuronal synapses have been associated with a broad spectrum of neurological disorders. Our proposal aims to investigate the molecular mechanisms that regulate synaptic connectivity in the hippocampus, a brain region that is essential for learning and memory. This basic research is expected to provide new and significant insights to wiring of the normal brain, and to facilitate the development of new effective treatments in humans.