Previous studies indicate a role for G1 active cyclin D2 (cD2) in the patterning and function of mammalian brain. Unexpected of a cell cycle protein, loss of cD2 leads to small brains and to selective loss of interneurons in the cerebellum. This project will examine cD2's role in the regulation of progenitor cell divisions and genesis of telencephalic interneurons. Pilot data indicate that, like the striking deficits in cerebellar granule and stellate neurons in this model, cD2-/- neocortex and hippocampus contain significantly fewer parvalbumin (Pv) containing interneurons while seeming to spare calretinin (CLR) and somatostatin (SSN) subtypes. These mice display rare spontaneous seizures and studies with Project 4 indicate cD2 nulls have a lower seizure threshold to drugs affecting GABAergic systems. Four hypotheses will be pursued in four Specific Aims: 1. cD2 regulates the number and differentiation of selected neural precursors in cerebral cortex. Experiments will determine: a. cD2 expression mapped during histogenesis of the telencephalon. b. which progenitor pools are most affected in cD2 null brain. c. which neuronal types are dependent upon cD2 expression during histogenesis. 2. Reduced cell division can affect subpopulations of cortical interneurons disproportionately. The interneuron subtypes lost in cD2-/- will be identified and compared with projection neuron populations. 3. cD2 promotes symmetric progenitor divisions, favoring the secondary proliferative population, to keep precursors in cycle that would otherwise exit. Studies will use: a. time-lapse imaging of progenitors in slice cultures from WT, cD2-/- and cD1-/- mice (in collaboration with Project 3). b. acute over- and under-expression of cD2 protein in vivo and in vitro. 4. Conditional loss of cD2 can be used to probe cortical vs. subcortical contributions of cD2 to brain structure and behavior. A floxP cD2 mouse will be produced and used to inactivate cD2 in MGE or neocortex/hippocampus. a. structural consequences will be examined in Project 1. b. behavioral studies will be pursued in Project 4.
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