Excitability Changes Related to GABAAReceptor Plasticity during Pregnancy

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Abstract
Alterations in GABAAreceptor (GABAAR) expression and function, similar to those we described previously during pregnancy in the mouse dentate gyrus, may also occur in other brain regions. Here we show, using immunohistochemical techniques, a decreased δ subunit-containing GABAAR (δGABAAR) expression in the dentate gyrus, hippocampal CA1 region, thalamus, and striatum but not in the cerebral cortex. In the face of the highly elevated neurosteroid levels during pregnancy, which can act on δGABAARs, it may be beneficial to decrease the number of neurosteroid-sensitive receptors to maintain a steady-state level of neuronal excitability throughout pregnancy. Consistent with this hypothesis, the synaptic input/output (I/O) relationship in the dentate gyrus molecular layer in response to lateral perforant path stimulation was shifted to the left in hippocampal slices from pregnant compared with virgin mice. The addition of allopregnanolone, at levels comparable with those found during pregnancy (100 nm), shifted the I/O curves in pregnant mice back to virgin levels. There was a decreased threshold to induce epileptiform local field potentials in slices from pregnant mice compared with virgin, but allopregnanolone reverted the threshold for inducing epileptiform activity to virgin levels. According to these data, neuronal excitability is increased in pregnant mice in the absence of allopregnanolone attributable to brain region-specific downregulation of δGABAAR expression. In brain regions, such as the cortex, that do not exhibit alterations in δGABAAR expression, there were no changes in the I/O relationship during pregnancy. Similarly, no changes in network excitability were detected in pregnantGabrd−/−mice that lack δGABAARs, suggesting that changes in neuronal excitability during pregnancy are attributable to alterations in the expression of these receptors. Our findings indicate that alterations in δGABAAR expression during pregnancy result in brain region-specific increases in neuronal excitability that are restored by the high levels of allopregnanolone under normal conditions but under pathological conditions may result in neurological and psychiatric disorders associated with pregnancy and postpartum.