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，以及缺乏有效的治疗方法，因此必须促进对神经精神疾病（如精神分裂症）潜在的突触和回路机制的理解。抑制和兴奋（I/E）平衡的改变正在成为各种复杂脑障碍的基本统一原则，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、唐氏综合征、Rett综合征和脆性X染色体。I/E失衡通常由GABA能中间神经元的改变引起，特别是含有钙结合蛋白小清蛋白（PV）的中间神经元。PV中间神经元的转录失调和GABA能功能障碍是SZ患者死后组织中一致的发现。这些变化对突触和电路功能的影响还不清楚。在这个提议中，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平衡的改变。PGC-1 <$（过氧化物酶体增殖物激活受体？辅激活因子1是中间神经元中调节P转录的转录辅激活因子。小鼠中PGC-1的遗传缺失导致中间神经元中PV表达降低和GABA能抑制的改变。因此，PGC-1是SZ中PV降低的潜在介导剂。此外，PGC-1的基因与SZ和双相情感障碍有关。PGC-1-/-小鼠提供了一种方法来研究由中间神经元中的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。我们将确定PGC-1缺陷小鼠抑制功能障碍的机制，以及对I/E平衡动态和海马回路功能的总体影响。此外，我们将利用I/E平衡的药理学和光遗传学操纵作为恢复PGC-1缺陷小鼠I/E平衡的手段，并确定对回路功能的影响。这些研究将极大地促进我们对转录调节异常引起的抑制性功能障碍的理解。 海马I/E平衡的动态变化。这将为纠正I/E失衡提供新的策略或治疗靶点，并对SZ和涉及I/E失衡和回路功能障碍的广泛其他复杂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-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.