Excitability changes related to GABAA receptor plasticity during pregnancy.
Alterations in GABA(A) receptor (GABA(A)R) 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 delta subunit-containing GABA(A)R (deltaGABA(A)R) 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 deltaGABA(A)Rs, 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 deltaGABA(A)R expression. In brain regions, such as the cortex, that do not exhibit alterations in deltaGABA(A)R expression, there were no changes in the I/O relationship during pregnancy. Similarly, no changes in network excitability were detected in pregnant Gabrd(-/-) mice that lack deltaGABA(A)Rs, suggesting that changes in neuronal excitability during pregnancy are attributable to alterations in the expression of these receptors. Our findings indicate that alterations in deltaGABA(A)R 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.
Maguire
Jamie
J
Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, California 90095-7332, USA.
Ferando
Isabella
I
Simonsen
Charlotte
C
Mody
Istvan
I
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001921:Brain / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011189:Potassium Chloride / Q000378:metabolism; D011247:Pregnancy; D011280:Pregnanolone / Q000172:deficiency / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
D011963:Receptors, GABA-A; D011189:Potassium Chloride; D011280:Pregnanolone