Transcriptional dysregulation causes altered modulation of inhibition by haloperidol
Transcriptional dysregulation causes altered modulation of inhibition by haloperidol
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DOI：
10.1016/j.neuropharm.2016.07.034
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发表时间：
2016-12-01
影响因子：
4.7
通讯作者：
Dobrunz, Lynn E.
中科院分区：
文献类型：
--
作者：
Brady, Lillian J.;Bartley, Aundrea F.;Dobrunz, Lynn E.
许多神经精神和神经发育障碍，如精神分裂症和自闭症涉及中间神经元转录失调。转录辅激活因子PGC-1 α调节GABA能中间神经元中的基因表达，这对于调节海马网络活动是重要的。PGC-1 α基因缺失导致小清蛋白表达减少，与精神分裂症死后组织中观察到的相似。我们的实验室先前已经表明，PGC-1 α（-/-）小鼠对CA 1锥体细胞具有增强的GABA能抑制，这增加了抑制/兴奋（I/E）比，改变了海马回路功能，并损害了海马依赖性行为。典型的抗精神病药物氟哌啶醇是一种对D2样受体具有选择性的多巴胺受体拮抗剂，先前已显示可增加海马CM区的兴奋。因此，我们测试了氟哌啶醇是否可以使PGC-1 α（-/-）小鼠CA 1的I/E平衡正常化，从而潜在地改善回路功能和行为。令人惊讶的是，我们发现，相反，由PGC-1 α的损失引起的中间神经元转录失调改变了氟哌啶醇对海马突触传递和电路功能的影响。氟哌啶醇急性给药可导致PGC-1 α（+/+）小鼠脑片中CA 1抑制解除，并降低CA 1锥体细胞的I/E比，但对PGC-1 α（-/-）小鼠无影响。在PGC-1 α（+/+）小鼠切片中，氟哌啶醇可增加通过电压敏感染料成像评估的CA 1活性扩散;然而，氟哌啶醇可降低PGC-1 α（-/）-小鼠切片中的活性扩散。氟哌啶醇增加了PGC-1 α（+/+）小鼠切片中海马γ振荡的功率，但降低了PGC-1 α（-/-）小鼠切片中γ振荡的功率。在pGC-1 alpha（+/+）小鼠中，氟哌啶醇抑制了巢构建，这是一种先天的海马依赖性行为，但在PGC-1 alpha（-/-）小鼠中则没有，因为它们已经有了受损的巢构建。在PGC-1 α（+/+）小鼠的切片中，氟哌啶醇的作用被D2受体拮抗剂模拟和阻断，在PGC-1 α（-/-）小鼠的切片中，阻断D2受体的作用丧失，尽管D2受体转录水平没有变化。总之，我们的研究结果表明，海马抑制性突触传递，CM电路功能，海马依赖性行为的抗精神病药物氟哌啶醇调制，这些影响氟哌啶醇在PGC-1 α（-/-）小鼠丢失。这些结果对治疗PGC-1 α缺乏症患者具有重要意义。(C)2016爱思唯尔有限公司版权所有
Many neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism involve interneuron transcriptional dysregulation. The transcriptional coactivator PGC-1 alpha regulates gene expression in GABAergic interneurons, which are important for regulating hippocampal network activity. Genetic deletion of PGC-1 alpha causes a decrease in parvalbumin expression, similar to what is observed in schizophrenia postmortem tissue. Our lab has previously shown that PGC-1 alpha(-/-) mice have enhanced GABAergic inhibition onto CA1 pyramidal cells, which increases the inhibition/excitation (I/E) ratio, alters hippocampal circuit function, and impairs hippocampal dependent behavior. The typical antipsychotic haloperidol, a dopamine receptor antagonist with selectivity for D2-like receptors, has previously been shown to increase excitation in the CM region of hippocampus. We therefore tested whether haloperidol could normalize the I/E balance in CA1 of PGC-1 alpha(-/-) mice, potentially improving circuit function and behavior. Surprisingly, we discovered instead that interneuron transcriptional dysregulation caused by loss of PGC-1 alpha alters the effects of haloperidol on hippocampal synaptic transmission and circuit function. Acute administration of haloperidol causes disinhibition in CA1 and decreases the I/E ratio onto CA1 pyramidal cells in slices from PGC-1 alpha(+/+) mice, but not PGC-1 alpha(-/-) mice. The spread of activity in CA1, assessed by voltage sensitive dye imaging, is increased by haloperidol in slices from PGC-1 alpha(+/+) mice; however haloperidol decreases the spread of activity in slices from PGC-1 alpha(-/)- mice. Haloperidol increased the power of hippocampal gamma oscillation in slices from PGC-1 alpha(+/+) mice but reduced the power of gamma oscillations in slices from PGC-1 alpha(-/-) mice. Nest construction, an innate hippocampal-dependent behavior, is inhibited by haloperidol in pGC-1 alpha(+/+) mice, but not in PGC-1 alpha(-/-) mice, which already have impaired nest building. The effects of haloperidol are mimicked and occluded by a D2 receptor antagonist in slices from PGC-1 alpha(+/+) mice, and the effects of blocking D2 receptors are lost in slices from PGC-1 alpha(-/-) mice, although there is no change in D2 receptor transcript levels. Together, our results show that hippocampal inhibitory synaptic transmission, CM circuit function, and hippocampal dependent behavior are modulated by the antipsychotic haloperidol, and that these effects of haloperidol are lost in PGC-1 alpha(-/-) mice. These results have implications for the treatment of individuals with conditions involving PGC-1 alpha deficiency. (C) 2016 Elsevier Ltd. All rights reserved.