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: 8830477
• 负责人: LYNN E DOBRUNZ
• 金额: $ 36.63万
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8830477
• 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（由适用提供）：由于神经精神疾病对人类健康的影响增强以及有效治疗的稀缺性，因此必须促进对神经精神疾病（如精神分裂症）的突触和电路机制的理解。抑制和兴奋平衡（I/E）的平衡改变正在成为一种基本的统一原则，其基本的原则是各种各样的复杂脑部疾病，包括神经精神疾病和神经发育疾病，精神分裂症，双极障碍，双极障碍，自闭症，自闭症，唐氏综合症，综合症和imm nesery是IMIMENNE，IMIMBER，IMIMIMEN，IMIMIMEN，IMIMPLAIMS。含有钙结合蛋白白蛋白（PV）的神经元。 PV中神经元和GABA能功能障碍的转录失调是SZ患者验尸组织的一致发现。这些变化对突触和电路功能的影响尚不清楚。在该提案中，我们将研究由PGC-1的遗传缺失引起的动物抑制功能障碍动物模型中动态I/E平衡的变化。 PGC-1（过氧化物组增殖物激活受体？共激活因子1€）是否在中间神经元中的转录共激活剂调节小鼠PGC-1遗传缺失的转录会导致中间神经元的PV表达降低，并且在GABA能抑制中的变化。因此，PGC-1是SZ中看到的PV降低的潜在介体。此外，PGC-1。与SZ和双相情感障碍有关。 PGC-1€ - / - 小鼠提供了一种研究中神经元中的转录功能障碍引起的神经元功能障碍引起的多因素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基础机制，以及对I/E平衡动力学和海马电路功能的总体影响。此外，我们将利用对I/E平衡的药物和光学遗传操纵，作为恢复PGC-1质量破裂小鼠的I/E平衡的一种手段，并确定对电路功能的影响。拟议的研究将大大提高我们对由于经骑术失调对抑制性功能障碍对抑制性功能障碍的影响的理解。 海马中I/E平衡的动力学。这将提供有关纠正I/E失衡的新策略或治疗靶标的见解，对治疗SZ的治疗以及涉及I/E失衡和电路功能障碍的其他广泛的复杂脑部疾病的影响。