Interneuron Dysfunction Alters the Dynamics of the Inhibition-Excitation Balance

中间神经元功能障碍改变了抑制-兴奋平衡的动态

• 批准号: 8496127
• 负责人: LYNN E DOBRUNZ
• 金额: $ 35.16万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496127
• 关键词: Affect; Animal Model; Anxiety; Area; Autistic Disorder; Autopsy; Bipolar Disorder; Brain Diseases; Calcium-Binding Proteins; Complex; Data; Disease; Down Syndrome; Drug Design; Equilibrium; Excitatory Synapse; Fragile X Syndrome; Functional disorder; Genes; Genetic; Genetic Transcription; Health; Hippocampus (Brain); Human; Inhibitory Synapse; Interneuron function; Interneurons; Ketamine; Knowledge; Lead; Maps; Mediating; Mediator of activation protein; Mental Depression; Messenger RNA; Mus; National Institute of Mental Health; Nature; Neurodevelopmental Disorder; Parvalbumins; Patients; Peroxisome Proliferator-Activated Receptors; Phencyclidine; Proteins; Rett Syndrome; Schizophrenia; Synapses; Synaptic Transmission; Tissues; Transcript; Work; cognitive function; drug of abuse; drug testing; effective therapy; gamma-Aminobutyric Acid; insight; nervous system disorder; neural circuit; neuropsychiatry; novel therapeutics; optogenetics; research study; response; therapeutic target

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.

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-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。PGC-1(过氧化物酶体增殖物激活受体？辅活化子1？)是中间神经元中的一种转录共激活物，调节P的转录。在小鼠中，PGC-1的基因缺失导致中间神经元中PV的表达减少和GABA能抑制的改变。因此，PGC-1？是深圳PV降低的一个潜在的介体。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多因素对突触和电路功能的影响的方法，该效应是由中间神经元转录失调引起的。我们将确定PGC-1基因缺陷小鼠抑制功能障碍的机制，以及对I/E平衡动力学和对海马回路功能的整体影响。此外，我们将利用I/E平衡的药理学和光遗传学操作作为一种手段来恢复PGC-1基因缺陷小鼠的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。