| Ovarian hormone fluctuations are a hallmark of reproductive function in mammals. However, these hormones also serve a role in regulating the excitability of the hippocampus, a pivotal structure that enables learning. THP (3alpha-OH-5[alpha]beta-pregnan-20-one) is a neuroactive steroid that acts as a potent positive modulator of most GABAA receptors (GABARs). In addition to modulating GABA-gated current, steroid fluctuations also induce alterations in GABAR subunit composition. The effect of the GABAR subunit switch on learning is not well established. I utilized electron microscopic immunocytochemistry (EM-ICC) to detect changes in expression of alpha4betadelta GABARs at the onset of puberty and across the estrous cycle of female mice. alpha4betadelta GABARs are expressed extrasynaptic to GABAergic input, and mediate a tonic inhibitory current, which is temporally and spatially dissociated from individual synaptic events. I found that at pubertal onset, expression of alpha4betadelta GABARs increased on the apical dendritic spines and shafts of CA1 hippocampal pyramidal neurons. Using a hippocampus-dependent spatial learning task, I found that alpha4betadelta GABARs compromised spatial learning at puberty, as evidenced by a recovery of learning in pubertal alpha4 knockout (KO) mice. Changes in GABAR subunit composition also occurred across the mouse estrous cycle. I observed increased alpha4betadelta GABAR expression on proestrus. Much like at the onset of puberty, alpha4betadelta GABAR expression reduced spatial learning on early proestrus. However, on late proestrus, circulating THP levels were high. THP has a reverse effect on alpha4betadelta GABARs, reducing outward GABA-gated inhibitory current. This reduced inhibition resulted in increased spatial learning. The role of alpha4betadelta GABARs in early proestrus learning deficits and late proestrus learning enhancements was confirmed by a recovery in learning in alpha4 KO mice on early proestrus, and a decrease in learning upon interference of THP's decrease of GABA-gated current through alpha4betadelta GABAR on late proestrus. These studies demonstrate that the hormone fluctuations observed at puberty and across the estrous cycle trigger alpha4betadelta GABARs expression, which impairs learning, an effect that is reversed by the stress steroid THP. |
