Cortical interneurons (INs) are well known to sculpt activity within the cortex. While the majority of effort to examine these cell types has centered on the MGE-derived basket and Martinotti cells, we have recently shown that the CGE-derived populations comprise 30% of all cortical interneurons and represent 60% of the interneurons in the superficial layers of the cortex. In this proposal, we focus on these populations, which we have recently shown uniformly express the SHTSaR ionotropic serotonin receptor.
Our first aim will employ a novel method for labeling the monosynaptic connections of this population and will provide an understanding of the development and function of the circuits in which these cells are embedded. With this in hand, we will study the combined contribution of genes and activity in the generation and integration of these interneurons into the developing neocortex. This work builds upon preliminary findings in the Fishell laboratory indicating that the transcription factor Prox1 is central to the specification and maturation of this population of interneurons.
The second aim of this proposal is to explore the role of Prox1 in the development and specification of these interneurons. These studies will be related to its impact on SHT3aR+ interneuron development by examining through imaging and physiological analysis how conditional targeted mutation of Prox1 gene function impacts the development, connectivity and function of this population. A central feature that characterizes SHT3aR+ interneurons is that they integrate into the cortex at a time when early network activity has already been initiated. In the third aim of this proposal, we will begin to explore the contributions of these early postnatal activities on SHT3aR+ interneuron development by examining how the maturation of the five major subclasses of interneurons are impacted by perturbations in excitatory activity during development and again how and whether this results in changes in their synaptic connectivity. These studies will thus provide a comprehensive understanding of how developmental gene expression and early activity contribute to the maturation of these understudied and underappreciated interneurcin subtypes.

Public Health Relevance

GABAergic INs is critical for the normal and pathological function of the brain. This Program Project will investigate the roles of SHTSaR INs;the least understood but largest population of GABAergic neurons in superficial cortical layers, on the development, function, and plasticity of the cerebral cortex. This component of the PPG will provide an understanding of how developmental gene expression and early activity contribute to the maturation of these neurons.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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Wamsley, Brie; Fishell, Gord (2017) Genetic and activity-dependent mechanisms underlying interneuron diversity. Nat Rev Neurosci 18:299-309
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