GABAergic contributions to neural circuit deficits in schizophrenia

描述(由申请人提供)：遗传因素似乎在精神分裂症的病因中发挥了重要作用，精神分裂症是一种破坏性的精神疾病，影响到全球1%的人口。最近的证据表明，大脑中GABA能抑制中间神经元的破坏是一个强有力的潜在机制。因此，我们的长期目标是了解抑制性功能障碍在这种精神疾病的病理生理学中的作用。识别发育过程中抑制性失调导致皮质功能紊乱的机制将有助于深入了解精神分裂症潜在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。人类筛选研究发现，神经调节蛋白-1(NRG-1)，一种细胞外信号因子，及其膜结合受体ERBB4(ErbB4)，是精神分裂症的强烈候选基因。大多数证据表明，ErbB4蛋白主要在大脑中的GABA能细胞中表达。ErbB4的整体干扰导致大脑皮层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，它可以在这种复杂的疾病中研究抑制性神经元间调节障碍在皮质网络扰动中的细胞类型特异性作用。利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上。相比之下，精神分裂症患者的认知和感知过程被破坏，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 体内初级视皮层回路中ErbB4缺失模型对精神分裂症的影响。健康视皮层中的突触和电路功能以及这些电路对视觉处理的贡献得到了很好的表征，为解释与疾病相关的细胞和网络功能变化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质功能的基本视觉处理和知觉方面表现出特定的缺陷。我们将结合细胞内和细胞外的记录以及细胞类型特定的光遗传操作来测试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。通过在突触和回路水平上测量皮层回路功能的关键方面，我们将评估ErbB4信号在抑制性和兴奋性神经元之间相互作用中的作用。我们将进一步使用有针对性的遗传方法来研究这一信号通路在特定群体的GABA能细胞存活和成熟中的发育作用。这些研究将揭示精神分裂症这一遗传模型中潜在的电路功能障碍的基本机制，并导致更完整地理解GABA能功能障碍在精神疾病中的细胞类型特定作用。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元素，我们的结果将适用于整个大脑系统。

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.