This PPG examines genetic regulation of brain formation and function from the perspective of cortical interneuron development. Increasing evidence suggests that selective developmental interneuron deficits are intimately linked with,failure of neural progenitor proliferation and specification. Lost function of the cell cycle gene cyclin D2 results in reduced brain volumes and selective loss of interneurons, e.g. cerebellar stellate and granule neurons, while sparing basket and Golgi interneurons as well as projection (Purkinje) neurons (Ross, Projl). Studies of neurogenic divisions in the cerebral cortical VZ suggest that GABAergic interneurons influence proliferation and differentiation of cortical neural cells (Kriegstein, ProjS). Evidence in rodent models suggests that most cortical interneurons originate from the medial ganglionic eminence (MGE) (Anderson, Proj2);thus investigations of interneuron development must involve MGE. The goal of the Program is to tease out the relative contributions of inteneuronal populations to brain formation, structure and function, examining the role of proliferation and interneuron specification to brain development. Project 1 will examine the consequences of reduced cell proliferation in brains of mice lacking cyclin D2, associated with small telencephalon and selective interneuron deficits. Conditional knockouts of cyclin D2 that further restrict the neural cell populations affected will be used to examine the dynamic role of specific neural subpopulations in brain formation. Project 2 will pursue the roles of Shh signaling to 1) specify cortical interneurons that originate in the MGE, and 2) (collaborating with Project 3) to regulate proliferation within the cortex. Several Cre-loxP conditional nulls will be examined with distinct patterns inactivating Shh or its receptor in the embryonic forebrain. These mice and in vitro studies will be used to explore the multiple roles of Shh on cortical neurogenesis. Project 3 will examine the dynamic behavior of neurogenic divisions in the VZ and SVZ of the MGE compared to cortex to determine how intrinsic and epigenetic factors modulate neurogenesis, and how regional alterations in the pattern of division might contribute to developmental interneuron deficits. Project 4 will examine the neurophysiology and behavioral consequences of the selective alterations of interneuronal subpopulations in animal models produced by Projects 1 and 2. The Projects are supported by administrative, statistical, histological and quantitative neuroanatomical services provided in Cores A and B. These genetic mouse models with highly selective interneuron deficits enable the Program to examine the contributions of neuron subsets to brain structure, complex behaviors and cognitive function. The proposed studies are relevant to epilepsy, schizophrenia, affective disorders and cognitive disorders including autism.
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