BACE1-NEUREGULIN-ErbB4 SIGNALING IN OLFACTORY MODELS OF PSYCHOSIS

描述（由申请人提供）：精神分裂症患者表现出高度的嗅觉缺陷，可能至少部分是由嗅觉皮层及其连接的结构改变引起的。本课组对啮齿动物初级嗅觉（梨状）皮质结构可塑性相关的动物模型进行了近十年的研究，并建立了损伤和遗传模型来研究梨状皮质重塑。该建议的中心假设是，BACE1-神经调节蛋白1 (NRG1)- erbb4信号传导对梨状皮质的持续重塑至关重要，主要是通过影响基底前脑神经源性生态位的诱导和分化，这些过程的扰动可能导致精神分裂症的一些临床表现。本文探讨的主要机制是第一层gaba能中间神经元的激活和/或诱导迁移，尤其是在嗅觉损伤后。这些中间神经元为梨状皮质锥体层的重建奠定了基础。在Specific Aim 1中，我们建立了BACE1- NRG1在梨状皮质发育和病变诱导的可塑性（重塑）中的作用。在Aim 2中，我们探讨了涉及基底前脑gaba能中间神经元和神经源性龛的梨状重构的特定细胞和分子机制。总之，本文提出的实验将NRG1信号通路与精神分裂症相关动物模型中的gaba能皮质中间神经元联系起来。公共卫生相关性：精神分裂症是一种使人衰弱的精神疾病，其原因和机制一直很难破译。过去的一个主要问题是缺乏动物模型来改变基因表达或造成病变，然后跟踪行为并研究干预与结果之间的生物联系（机制）。这一重大障碍现在正开始消除，因为发现了导致疾病病因的易感基因，以及这些基因或其下游分子靶点表达发生改变的转基因动物的出现。在这项应用中，我们结合了嗅觉边缘系统神经可塑性的传统优势和转基因动物模型，提出至少一部分精神病症状可能是基于嗅觉皮层及其连接的可塑性停滞，这是由于gaba能皮层中间神经元信号不足造成的。

DESCRIPTION (provided by applicant): Schizophrenic patients show high-level olfactory deficits that may be caused, at least in part, by structural alterations in olfactory cortex and its connections. Our group has studied animal models relevant to the structural plasticity of the rodent primary olfactory (piriform) cortex for a decade and has established lesion and genetic models to study piriform cortex remodeling. The central hypothesis of this proposal is that BACE1- neuregulin 1 (NRG1)-ErbB4 signaling is critical for the ongoing remodeling of piriform cortex, primarily by affecting the induction and differentiation of basal forebrain neurogenic niches and that perturbations of these processes may cause some of the clinical manifestations of schizophrenia. The principal mechanism explored here is the activation and/or induced migration of GABAergic interneurons of layer I, especially evident after olfactory lesions. These interneurons then lay the groundwork for reconstitution of the pyramidal layer of piriform cortex. In Specific Aim 1, we establish the role of BACE1- NRG1 in the development and lesion- induced plasticity (remodeling) of piriform cortex. In Aim 2, we explore specific cellular and molecular mechanisms of piriform remodeling involving GABAergic interneurons and neurogenic niches in the basal forebrain. Together, experiments proposed here link NRG1 signaling pathways with GABAergic cortical interneurons in animal models relevant to schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a debilitating mental illness whose causes and mechanisms have been very difficult to decipher. A major problem in the past was the absence of animal models in which to alter the expression of genes or make lesions and then follow behaviors and study biological links (mechanisms) between interventions and outcomes. This significant obstacle is now starting to yield, with the discovery of susceptibility genes that contribute to the disease cause and the availability of transgenic animals with altered expression of these genes or their downstream molecular targets. In this application, we combine our traditional strengths in neural plasticity of the olfactory limbic system and in transgenic animal models and propose that at least a portion of psychotic symptoms may be modeled on the basis of a stalled plasticity of the olfactory cortex and its connections because of deficient signals in GABAergic cortical interneurons.