Maguire Jamie, Ferando Isabella, Simonsen Charlotte, Mody Istvan
Department of Neurology, The David Geffen School of Medicine, University of California, Los Angeles, California 90095-7332, USA.
J Neurosci. 2009 Jul 29;29(30):9592-601. doi: 10.1523/JNEUROSCI.2162-09.2009.
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.
γ-氨基丁酸A型受体（GABA(A)R）表达和功能的改变，类似于我们之前在小鼠齿状回孕期所描述的情况，也可能发生在其他脑区。在这里，我们使用免疫组化技术显示，在齿状回、海马CA1区、丘脑和纹状体中，含δ亚基的GABA(A)R（δGABA(A)R）表达减少，但在大脑皮层中未减少。鉴于孕期神经甾体水平大幅升高，而神经甾体可作用于δGABA(A)R，减少神经甾体敏感受体的数量可能有利于在整个孕期维持神经元兴奋性的稳态水平。与这一假设一致的是，与未孕小鼠相比，孕鼠海马切片中齿状回分子层对侧穿通路径刺激的突触输入/输出（I/O）关系向左偏移。添加与孕期水平相当（100 nM）的别孕烯醇酮后，孕鼠的I/O曲线恢复到未孕水平。与未孕小鼠相比，孕鼠切片中诱发性癫痫样局部场电位的阈值降低，但别孕烯醇酮将诱发性癫痫样活动的阈值恢复到未孕水平。根据这些数据，在没有别孕烯醇酮的情况下，孕鼠的神经元兴奋性增加，这归因于脑区特异性的δGABA(A)R表达下调。在大脑皮层等未表现出δGABA(A)R表达改变的脑区，孕期I/O关系没有变化。同样，在缺乏δGABA(A)R的孕Gabrd(-/-)小鼠中未检测到网络兴奋性的变化，这表明孕期神经元兴奋性的变化归因于这些受体表达的改变。我们的研究结果表明，孕期δGABA(A)R表达的改变导致脑区特异性的神经元兴奋性增加，在正常情况下，高水平的别孕烯醇酮可使其恢复，但在病理情况下，可能导致与妊娠和产后相关的神经和精神疾病。
