Interneuron Dysfunction Alters the Dynamics of the Inhibition-Excitation Balance

描述(申请人提供)：由于神经精神障碍对人类健康的巨大影响，以及缺乏有效的治疗方法，有必要促进对神经精神障碍(如精神分裂症)的突触和回路机制的了解。抑制与兴奋平衡(I/E)的改变正逐渐成为一种基本的统一原则，在许多复杂的大脑疾病中，包括精神分裂症、双相情感障碍、自闭症、唐氏综合征、Rett综合征和脆性X等神经精神障碍和神经发育障碍。I/E失衡通常是由GABA能中间神经元，特别是含有钙结合蛋白小蛋白(PV)的中间神经元的改变引起的。在SZ患者的死后组织中，PV中间神经元转录异常和GABA能功能障碍是一致的。这些变化对突触和回路功能的影响还不是很清楚。在这项建议中，我们将研究由pGC-1α基因缺失引起的抑制性功能障碍动物模型中动态I/E平衡的变化。PGC-1α(Peroxisome Profferator Actiated ReceptorγCoActiator 1α)是一种位于中间神经元的转录共激活因子，调节P的转录。在小鼠中，PGC-1α的基因缺失导致中间神经元PV表达减少和GABA能抑制改变。因此，pGC-1α是深圳地区PV降低的一个潜在的介导者。此外，PGC-1α基因与SZ和双相情感障碍有关。PGC-1α-/-小鼠为研究由中间神经元转录失调引起的神经元功能障碍对突触和回路功能的多因素影响提供了一种方法。我们将确定PGC-1α缺陷小鼠抑制功能障碍的机制，以及对I/E平衡动态和对海马回路功能的整体影响。此外，我们将利用药物和光遗传学的I/E平衡操作作为一种手段来恢复pGC-1α缺陷小鼠的I/E平衡，并确定由此对电路功能的影响。所提出的研究将极大地促进我们对转录失调所致的抑制功能障碍对 海马区I/E平衡的动态变化这将为纠正I/E失衡的新策略或治疗目标提供见解，并对SZ和涉及I/E失衡和电路功能障碍的广泛其他复杂大脑疾病的治疗产生影响。

DESCRIPTION (provided by applicant): Because of the enormous impact of neuropsychiatric disorders on human health, and the scarcity of effective treatments, it is essential to advance the understanding of the synaptic and circuit mechanisms underlying neuropsychiatric disorders such as schizophrenia. Alteration in the balance of inhibition and excitation (I/E) is emerging as a fundamental unifying principle underlying a wide variety of complex brain disorders, including neuropsychiatric and neurodevelopmental disorders such as schizophrenia, bipolar disorder, autism, Down Syndrome, Rett Syndrome and Fragile X. I/E imbalance is often caused by alterations in GABAergic interneurons, particularly interneurons containing the calcium binding protein parvalbumin (PV). Transcriptional dysregulation in PV interneurons and GABAergic dysfunction are consistent finding in postmortem tissue of SZ patients. The effects of these changes on synaptic and circuit function are not well understood. In this proposal we will investigate alterations in the dynamic I/E balance in an animal model of inhibitory dysfunction caused by genetic deletion of PGC-1α. PGC-1α (peroxisome proliferator activated receptor γ coactivator 1α) is a transcriptional co-activator in interneurons that regulates transcription of P. Genetic deletion of PGC-1α in mice results in decreased expression of PV in interneurons and alterations in GABAergic inhibition. PGC-1α is therefore a potential mediator of the decreased PV seen in SZ. In addition, the gene for PGC-1α is associated with SZ and bipolar disorder. PGC-1α-/- mice provide a way to investigate the multi-factorial effects on synaptic and circuit function of interneuron dysfunction cause by transcriptional dysregulation in interneurons. We will determine the mechanisms underlying the inhibitory dysfunction in PGC-1α deficient mice, as well as the overall effects on the dynamics of the I/E balance and on hippocampal circuit function. In addition, we will utilize pharmacological and optogenetic manipulation of the I/E balance as a means to restore the I/E balance in PGC-1α deficient mice, and determine the resulting effects on circuit function. The proposed studies will greatly advance our understanding of the effects of inhibitory dysfunction due to transcripitional dysregulation on the dynamics of I/E balance in hippocampus. This will provide insights into new strategies or therapeutic targets for correcting I/E imbalances, with implications for treatment of SZ and a wide range of other complex brain disorders involving I/E imbalance and circuit dysfunction.