GABAergic contributions to neural circuit deficits in schizophrenia

GABAergic 对精神分裂症神经回路缺陷的贡献

基本信息

批准号：
9206190
负责人：
JESSICA A CARDIN
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9206190
关键词：
Adolescent Affect Animals Behavioral Biological Neural Networks Brain Candidate Disease Gene Cells Cerebral cortex Cognition Cognitive Complex Data Development Disease Disinhibition Electrophysiology (science)Elements Embryo ErbB4 Receptor Protein Tyrosine Kinase Etiology Exhibits Foundations Frequencies Functional disorder Generations Genetic Genetic Models Goals Human Hyperactive behavior Impaired cognition Impairment In Vitro Inhibitory Synapse Interneuron function Interneurons Knowledge Lead Link Measurement Membrane Mental disorders Methods Modeling Mus Neuregulin 1 Neurons Neurophysiology - biologic function Parvalbumins Patients Perception Play Population Process Pyramidal Cells Recruitment Activity Role Schizophrenia Sensory Shapes Short-Term Memory Signal Pathway Signal Transduction Somatostatin Synapses System Testing Time Visual Cortex Visual Perception Work area striata awake base brain cell cell type cellular targeting excitatory neuron experimental study extracellular gamma-Aminobutyric Acid genetic approach in vivo inhibitory neuron innovation insight migration mouse model neural circuit novel novel therapeutic intervention operation optogenetics postnatal postsynaptic prepulse inhibition public health relevance receptor binding reuptake screening sensory integration spatial memory synaptic inhibition synaptogenesis targeted treatment visual processing

项目摘要

DESCRIPTION (provided by applicant): Genetic factors appear to play a major role in the etiology of schizophrenia, a devastating mental illness that affects up to 1% of the worldwide population. Recent evidence suggests disruption of GABAergic inhibitory interneurons in the brain as a strong candidate underlying mechanism. Our long-term goal is therefore to understand the role of inhibitory dysfunction in the pathophysiology of this psychiatric disease. Identifying the mechanisms by which inhibitory dysregulation during development leads to perturbation of cortical function will give insight into the neurodevelopmental cellular mechanisms underlying schizophrenia and may provide new cellular targets for therapeutic strategies. Human screening studies have identified Neuregulin-1 (Nrg-1), an extracellular signaling factor, and its membrane-bound receptor ERBB4 (ErbB4), as strong candidate genes for schizophrenia. Most evidence indicates that ErbB4 protein is expressed predominantly in GABAergic cells throughout the brain. Global disruptions of ErbB4 result in decreased GABA release in the cerebral cortex, and mice lacking Nrg-1 or ErbB4 exhibit key behavioral deficits associated with schizophrenia. The ErbB4 model of schizophrenia is thus an ideal system in which to examine the cell type-specific role of inhibitory interneuron dysregulation in cortical network perturbation in this complex disorder. A major issue in using genetic mouse models to study psychiatric disease has been that many studies focus on single cells or synapses in vitro. In contrast, the cognitive and perceptual processes disrupted in schizophrenia rely on large-scale neural network interactions in the intact brain. We will therefore examine neural function in vivo in primary visual cortex circuits in the ErbB4 deletion model of schizophrenia. Synaptic and circuit function in the healthy visual cortex and the contribution of these circuits to visual processing are well characterized, providing a critical framework in which to interpret disease-related alterations in cellular and network function. Furthermore, schizophrenic patients exhibit specific deficits in basic visual processing and perception that rely on primary visual cortex function. We will use a combination of intra- and extracellular recordings and cell type-specific optogenetic manipulations to test the impact of ErbB4 deletion on the function of inhibitory interneurons in cortical networks in vivo in awake behaving animals. Using measurements of key aspects of cortical circuit function at the synaptic and circuit levels, we will assess the rol of ErbB4 signaling in interactions between inhibitory and excitatory neurons. We will further use targeted genetic approaches to examine the developmental role of this signaling pathway in the survival and maturation of specific populations of GABAergic cells. These studies will reveal fundamental mechanisms underlying circuit dysfunction in this genetic model of schizophrenia and lead to a more complete understanding of the cell type-specific role of GABAergic dysfunction in psychiatric disease. Because the cellular and circuit interactions identified in thi work are core elements of neural function, our results will be applicable to systems throughout the brain.

描述（由申请人提供）：遗传因素似乎在精神分裂症的病因学中发挥着重要作用，精神分裂症是一种毁灭性的精神疾病，影响着全球多达 1% 的人口。最近的证据表明，大脑中 GABA 能抑制性中间神经元的破坏是一个强有力的候选潜在机制。因此，我们的长期目标是了解抑制功能障碍在这种精神疾病的病理生理学中的作用。确定发育过程中抑制性失调导致皮质功能扰动的机制将有助于深入了解精神分裂症的神经发育细胞机制，并可能为治疗策略提供新的细胞靶点。人类筛选研究已确定细胞外信号因子 Neuregulin-1 (Nrg-1) 及其膜结合受体 ERBB4 (ErbB4) 是精神分裂症的强有力候选基因。大多数证据表明 ErbB4 蛋白主要在整个大脑的 GABA 细胞中表达。 ErbB4 的整体破坏导致大脑皮层 GABA 释放减少，缺乏 Nrg-1 或 ErbB4 的小鼠表现出与精神分裂症相关的关键行为缺陷。因此，精神分裂症的 ErbB4 模型是一个理想的系统，用于检查抑制性中间神经元失调在这种复杂疾病的皮质网络扰动中的细胞类型特异性作用。使用遗传小鼠模型研究精神疾病的一个主要问题是许多研究都集中在体外的单细胞或突触。相比之下，精神分裂症中受损的认知和知觉过程依赖于完整大脑中的大规模神经网络相互作用。因此，我们将检查神经功能精神分裂症 ErbB4 缺失模型中初级视觉皮层回路的体内研究。健康视觉皮层中的突触和回路功能以及这些回路对视觉处理的贡献得到了很好的表征，为解释细胞和网络功能中与疾病相关的改变提供了一个关键框架。此外，精神分裂症患者在依赖初级视觉皮层功能的基本视觉处理和感知方面表现出特定的缺陷。我们将结合细胞内和细胞外记录以及细胞类型特异性光遗传学操作来测试 ErbB4 缺失对清醒行为动物体内皮质网络中抑制性中间神经元功能的影响。通过测量突触和回路水平上皮质回路功能的关键方面，我们将评估 ErbB4 信号传导在抑制性神经元和兴奋性神经元之间相互作用中的作用。我们将进一步使用靶向遗传方法来检查该信号通路在特定 GABA 细胞群的存活和成熟中的发育作用。这些研究将揭示精神分裂症遗传模型中回路功能障碍的基本机制，并导致人们更全面地了解 GABA 能功能障碍在精神疾病中的细胞类型特异性作用。由于这项工作中确定的细胞和电路相互作用是神经功能的核心要素，因此我们的结果将适用于整个大脑的系统。