Sex differences in Purkinje cell sensitivity to ischemia

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DESCRIPTION (provided by applicant): Stroke or Brain Attack is a sexually dimorphic disease. Women enjoy protection from stroke relative to men, in part due to endogenous levels of sex steroids, the estrogens and progesterone. While estrogen has been well studied, little is known about progesterone's neuroprotective properties. The steroid is an important but controversial component of hormone therapy in women. Progesterone reduces ischemic brain injury in vivo, however .the mechanism is not known. We hypothesize that one important mechanism of neuroprotection is via progesterone's enhancement of GABA-A receptor activity, counteracting the high levels of excitatory input to neurons during and immediately following ischemia. This R21 application tests this overarching hypothesis, using whole cell voltage-clamp experiments and single cell PCR in cerebellar Purkinje cell (PC) culture, as a novel and initial step in understanding progesterone's neurophysiological actions in complex animal ischemia models. We focus on PCs because of important early observations that PCs, like the well-studied hippocampal CA1 neuron, are uniquely hyper-vulnerable to ischemia. While data from these GABA sensitive cells and cerebral ischemia are few, our recent studies emphasize that non-ischemic female PCs are selectively sensitive to enhancement of GABA-A receptor activity by progesterone metabolites. Furthermore, our preliminary data indicate that female mice require continued exposure of sex steroids to maintain enhanced sensitivity to progesterone metabolites relative to male mice. Therefore, we will test three specific hypotheses 1) Acute progesterone protects PCs from ischemia through activation of the GABA-A receptor. 2) Chronic progesterone enhances female cells to acute progesterone neuroprotection and 3) that chronic progesterone decreases the expression of the gamma-subumt of the GABA-A receptor resulting in increased sensitivity to acute progesterone. Our findings will begin to elucidate the cellular mechanisms of progesterone neuroprotection and sex differences in Purkinje cell response to ischemia.