XXXX acts through nuclear- and membrane-initiated mechanisms to maintain a balance between GABAergic and glutamatergic signaling in the brain: implications for hormone replacement therapy.

@entity172 @entity1 @entity308 @entity2227 @entity1246 @entity53 @entity134 @entity148
@entity53 (E2) is a potent neuroactive @entity134 that acts through both nuclear and membrane @entity172 receptors (ER) found widely distributed in the brain. Although long known for its role in the neural control of reproduction, more recent work demonstrates that E2 also affects learning and memory, as well as @entity148 and @entity308 . These findings prompted studies on the neural consequences of long-term E2 deprivation in postmenopausal @entity1 . Despite hundreds of studies in animal models and @entity1 , the advisability of hormone replacement therapy (HRT) for neuroprotection remains a contentious issue because the effects of @entity172 vary among studies. One difficulty in reconciling the conflicting results is the lack of integration across the neuroscience sub-disciplines that contribute to the field. To address this issue, we first review data on E2 regulation of cognition and mood, as well as on factors that may contribute to the disparate findings across studies. @entity1246 and @entity2227 are proximal regulators of cognition and mood; therefore we next review review data showing that E2 acts through nuclear- and membrane-initiated mechanisms to regulate @entity1246 and @entity2227 signaling, respectively. We also review evidence that these E2 signaling mechanisms change with age. Finally, we propose a molecular and cellular model of how E2 can have positive, negative, or no effects on neural functions in the aging brain, and we highlight the current gaps in the literature. Addressing these gaps will facilitate development of the mechanism-based strategies needed for designing more effective HRT regimens.
