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: 9050707
• 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 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9050707
• 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; PPAR gamma; Parvalbumins; Patients; Phencyclidine; Proteins; Rett Syndrome; Schizophrenia; Synapses; Synaptic Transmission; Tissues; Transcript; Transcription Coactivator; Work; cognitive function; drug of abuse; drug testing; effective therapy; gamma-Aminobutyric Acid; insight; nervous system disorder; neural circuit; neuropsychiatric disorder; novel therapeutic intervention; 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-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.

描述（由申请人提供）：由于神经精神疾病对人类健康产生巨大影响，并且缺乏有效的治疗方法，因此有必要增进对精神分裂症等神经精神疾病背后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、双向情感障碍、自闭症、唐氏综合症、雷特综合症和脆性 X 病。I/E 不平衡通常是由 GABA 能中间神经元的改变引起的，特别是 中间神经元含有钙结合蛋白小白蛋白（PV）。在 SZ 患者死后组织中，PV 中间神经元的转录失调和 GABA 能功能障碍是一致的。这些变化对突触和电路功能的影响尚不清楚。在本提案中，我们将研究由 PGC-1α 基因缺失引起的抑制功能障碍动物模型中动态 I/E 平衡的变化。 PGC-1α（过氧化物酶体增殖物激活受体 γ 共激活因子 1α）是中间神经元中的转录共激活因子，可调节 P 的转录。小鼠中 PGC-1α 的基因缺失会导致中间神经元中 PV 表达的降低以及 GABA 能抑制的改变。因此，PGC-1α 是 SZ 中 PV 下降的潜在调节因素。此外，PGC-1α 基因与精神分裂症和双相情感障碍有关。 PGC-1α-/- 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回路功能的多因素影响的方法。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作作为恢复 PGC-1α 缺陷小鼠的 I/E 平衡的手段，并确定由此产生的对电路功能的影响。拟议的研究将极大地增进我们对转录失调导致的抑制功能障碍影响的理解。 海马体 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，对 SZ 和涉及 I/E 失衡和回路功能障碍的其他各种复杂脑部疾病的治疗具有影响。