Interneuron Dysfunction Alters the Dynamics of the Inhibition-Excitation Balance

描述（由申请人提供）：由于神经精神疾病对人类健康的巨大影响，以及有效治疗的缺乏，有必要推进对神经精神疾病（如精神分裂症）背后的突触和电路机制的理解。抑制和兴奋平衡（I/E）的改变正在成为多种复杂脑部疾病的基本统一原则，包括神经精神和神经发育障碍，如精神分裂症、双相情感障碍、自闭症、唐氏综合症、Rett综合征和脆性x。I/E失衡通常是由gaba能中间神经元的改变引起的，特别是含有钙结合蛋白小白蛋白（PV）的中间神经元。PV中间神经元的转录失调和gaba能功能障碍在SZ患者死后组织中是一致的。这些变化对突触和神经回路功能的影响尚不清楚。在这项提议中，我们将研究PGC-1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。过氧化物酶体增殖物激活受体？coactivator 1¿)是调节P.转录的中间神经元中的转录共激活因子，在小鼠中基因缺失PGC-1¿会导致中间神经元中PV的表达减少和gaba能抑制的改变。因此，PGC-1¿是SZ中PV下降的潜在介质。此外，PGC-1¿基因与SZ和双相情感障碍有关。PGC-1¿-/-小鼠提供了一种研究中间神经元转录失调引起的中间神经元功能障碍对突触和电路功能的多因素影响的方法。我们将确定PGC-1缺失小鼠抑制性功能障碍的机制，以及对I/E平衡动力学和海马回路功能的总体影响。此外，我们将利用药理学和光遗传学操作I/E平衡作为恢复PGC-1缺陷小鼠I/E平衡的手段，并确定对电路功能的影响。所提出的研究将极大地促进我们对由于转录失调引起的抑制功能障碍对细胞的影响的理解

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-1¿. PGC-1¿ (peroxisome proliferator activated receptor ? coactivator 1¿) is a transcriptional co-activator in interneurons that regulates transcription of P. Genetic deletion of PGC-1¿ in mice results in decreased expression of PV in interneurons and alterations in GABAergic inhibition. PGC-1¿ is therefore a potential mediator of the decreased PV seen in SZ. In addition, the gene for PGC-1¿ is associated with SZ and bipolar disorder. PGC-1¿-/- 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-1¿ 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-1¿ 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.