Estradiol and raloxifene modulate hippocampal gamma oscillations during a spatial memory task.

Previous work suggests that estradiol regulates the expression of hippocampal parvalbumin as well as hippocampus-dependent spatial memory in mice. Parvalbumin interneurons generate neuronal oscillatory activity in the gamma frequency range (30-80Hz) and gamma oscillations are closely linked with higher cognitive functions. Raloxifene, a selective estrogen receptor modulator, shows beneficial effects on human cognitive performance, and has few peripheral side effects unlike estradiol, but the biological mechanisms which underpin these benefits are not clear. This study aimed to investigate whether estradiol and raloxifene modulate hippocampal gamma-band oscillations during spatial memory performance. Prepubescent female mice were ovariectomized (OVX) and implanted with a subcutaneous pellet of either estradiol (E2), raloxifene or placebo. During adulthood, local field potentials were recorded from the dorsal hippocampus while mice were performing the Y-maze hippocampus-dependent spatial memory task. Ovariectomy caused deficits in spatial memory, accompanied by a significant reduction in hippocampal gamma oscillations, specifically during decision making. Estradiol as well as raloxifene rescued both behavioural and electrophysiological deficits. These data have significant implications for disorders of cognitive impairment where altered gamma oscillations are apparent, such as schizophrenia.