BACE1-NEUREGULIN-ErbB4 SIGNALING IN OLFACTORY MODELS OF PSYCHOSIS

精神病嗅觉模型中的 BACE1-神经调节蛋白-ErbB4 信号转导

• 批准号: 7803561
• 负责人: VASSILIS E. KOLIATSOS
• 金额: $ 20.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-13 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803561
• 关键词: Adult; Affect; Animal Model; Animals; Behavior; Behavioral; Biological; Clinical; Cognitive; Data; Development; Disease; ErbB4 gene; Gene Deletion; Gene Expression; Generations; Genetic Models; Genotype; Interneurons; Intervention; Lead; Lesion; Limbic System; Link; Maintenance; Mental disorders; Modeling; Molecular; Molecular Target; Mus; N-Methyl-D-Aspartate Receptors; Neuregulin 1; Neuregulins; Neuronal Plasticity; Olfactory Cortex; Outcome; Patients; Phenotype; Process; Psychotic Disorders; Rodent; Role; Schizophrenia; Signal Pathway; Signal Transduction; Structure; Study Section; Susceptibility Gene; Symptoms; Transgenic Animals; Work; basal forebrain; base; beta-site APP cleaving enzyme 1; computerized data processing; endophenotype; hippocampal pyramidal neuron; memory recognition; migration; neurogenesis; overexpression; paracrine; piriform cortex; public health relevance; reconstitution; research study; young adult

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.

描述(申请人提供)：精神分裂症患者表现出高水平的嗅觉缺陷，这可能至少部分是由嗅觉皮质及其连接的结构变化引起的。我们团队研究了十年来与啮齿动物初级嗅觉(梨状)皮质结构可塑性相关的动物模型，并建立了损伤和遗传模型来研究梨状皮质的重塑。该建议的中心假设是BACE1-neuRegin1(NRG1)-ErbB4信号在梨状皮质正在进行的重塑中起关键作用，主要是通过影响基底前脑神经源性小生境的诱导和分化，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激活和/或诱导GABA能中间神经元的迁移，尤其是在嗅觉损伤后。然后，这些中间神经元为梨状皮质锥体层的重建奠定了基础。在特定的目标1中，我们确定了BACE1-NRG1在梨状皮质发育和损伤诱导的可塑性(重塑)中的作用。在目标2中，我们探索了梨状重塑的特定细胞和分子机制，涉及基底前脑的GABA能中间神经元和神经源性壁龛。总之，这里提出的实验将NRG1信号通路与与精神分裂症相关的动物模型中的GABA能皮质中间神经元联系起来。与公共卫生相关：精神分裂症是一种衰弱的精神疾病，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的表达或造成损害，然后跟踪行为并研究干预和结果之间的生物学联系(机制)。随着导致疾病原因的易感基因的发现，以及这些基因或其下游分子靶标表达发生变化的转基因动物的出现，这一重大障碍现在开始出现。在这一应用中，我们结合了我们在嗅觉边缘系统和转基因动物模型的神经可塑性方面的传统优势，并提出至少部分精神病症状可以基于嗅皮层及其联系的可塑性停滞的基础上，因为GABA能皮质中间神经元中的信号不足。