Mechanisms of schizophrenia-like phenotypes in BACE 1 knockout mice

描述(由申请人提供)：？-SITE APP裂解酶(BACE1)裂解淀粉样前体蛋白(APP)作为产生淀粉样蛋白？的初始步骤。(a？？)多肽，它与阿尔茨海默病的发病机制有关。作为一种发育调节的天冬氨酸蛋白酶，BACE1具有APP以外的底物，提示BACE1具有多种生理功能。最近，BACE1-/-小鼠中枢和外周髓鞘形成的缺陷与BACE1依赖的神经调节蛋白1(NRG1)蛋白分解过程的改变有关。由于NRG1在基因上也与精神分裂症有关，我们测试了NRG1处理受损的BACE1-/-小鼠是否表现出精神分裂症样行为异常。我们证明BACE1-/-小鼠表现出被认为是精神分裂症症状的动物类似物的多种特征，包括脉冲前抑制缺陷、新奇诱导的多动、对谷氨酸能精神刺激剂(MK-801)的超敏、认知障碍和社会互动的改变。重要的是，其中一些症状对氯氮平治疗有反应。在BACE1-/-小鼠中，NRG1的受体ErbB4的表达没有改变，它可能是NRG1脑功能的主要中介，特别是与精神分裂症相关的功能。然而，BACE-/-小鼠大脑中ErbB4和PSD-95的关联性降低，表明ErbB4的突触池显著减少。与突触ErbB4在突触功能和脊椎形态中的作用相一致，BACE1-/-小鼠海马锥体神经元中的棘突密度降低。我们的发现表明，BACE1的遗传缺陷可以充分导致精神分裂症样内表型，导致NRG1/ErbB4信号的改变，这可能代表了精神分裂症和相关精神疾病发病的新机制。鉴于最近有报道称NRG1/ErbB4信号受损导致谷氨酸能功能低下与精神分裂症的发病机制有关，我们将检验BACE1依赖的NRG1/ErbB4信号损伤可以调节NMDA或AMPA受体通路(Aim1)的假设。在AIM2中，我们将使用RNA干扰作为一种策略，研究在发育或成年期开始抑制BACE1对成年小鼠精神分裂症样表型表达的影响。如果RNA干扰方法不能产生足够的BACE1抑制，将使用另一种方法(在BACE1缺失背景上有条件表达BACE1的小鼠模型)来调节不同发育阶段的BACE1水平。拟议的研究将对识别与精神分裂症样内表型有关的BACE1相关细胞通路和神经回路具有重要意义。公共卫生相关性：精神分裂症是一种严重的慢性精神疾病，全球终生患病率为0.12-1.6%。最令人兴奋的是最近精神分裂症与特定基因的关联，例如neuRegin1，然而这种关联的确切机制尚不清楚。我们的发现表明，依赖于BACE1的NRG1信号的改变导致了精神分裂症的表型，并在精神分裂症和相关精神疾病的发病机制中暗示了一种新的分子机制。鉴于最近有报道称NRG1信号受损导致谷氨酸能功能低下与精神分裂症的发病机制有关，我们将检验NRG1信号中BACE1依赖的损伤调节NMDA或AMPA受体通路的假设。通过使用RNA干扰和条件BACE1遗传模型，我们还将分析精神分裂症样表型的表达在多大程度上依赖于BACE1在发育和成年期的活性。

DESCRIPTION (provided by applicant): ?-site APP cleaving enzyme (BACE1) cleaves the amyloid precursor protein (APP) as the initial step in the production of the amyloid ? (A??) peptide, which is involved in the pathogenesis of Alzheimer's disease. As a developmentally regulated aspartyl protease, BACE1 has been shown to have putative substrates other than APP, suggesting multiple physiological functions of BACE1. Recently, changes in BACE1-dependent proteolytic processing of neuregulin 1 (NRG1) have been linked to deficits in central and peripheral myelination in BACE1-/- mice. Because NRG1 has also been genetically linked to schizophrenia, we tested whether BACE1-/- mice with impaired processing of NRG1 show schizophrenia-like behavioral abnormalities. We demonstrate that BACE1-/- mice exhibit multiple features considered as animal analogues of schizophrenia symptoms including deficits in prepulse inhibition, novelty-induced hyperactivity, hypersensitivity to a glutamatergic psychostimulant (MK-801), cognitive impairments and alterations in social interactions. Importantly, some of these symptoms were responsive to clozapine treatment. The expression of ErbB4, a receptor of NRG1 and likely the main mediator of NRG1 functions in the brain, particularly those related to schizophrenia, was not changed in BACE1-/- mice. However, a synaptic pool of ErbB4 was significantly reduced as indicated by decreased association of ErbB4 and PSD-95 in the brains of BACE-/- mice. In accordance with the role of synaptic ErbB4 in synaptic function and spine morphology, BACE1-/- mice displayed reduced density of spines in hippocampal pyramidal neurons. Our findings indicate that schizophrenia-like endophenotypes can be sufficiently caused by genetic deficits of BACE1, leading to an alteration in NRG1/ErbB4 signaling that may represent a new mechanism in the pathogenesis of schizophrenia and related psychiatric disorders. Given recent reports that impaired NRG1/ErbB4 signaling leads to glutamatergic hypofunction implicated in mechanisms of schizophrenia, we will test the hypothesis that BACE1-dependent impairments in NRG1/ErbB4 signaling can modulate NMDA or AMPA receptor pathways (Aim1). In Aim2, we will use RNA interference as a strategy to study effects of BACE1 inhibition initiated during development or in adulthood on expression of schizophrenia-like phenotypes in adult mice. If the RNA interference approach fails to produce sufficient BACE1 inhibition, an alternative approach (mouse models with conditional expression of BACE1 on BACE1 null background) will be used to modulate the levels of BACE1 at different stages of development. The proposed studies will be important for the identification of BACE1-related cellular pathways and neural circuits that are involved in schizophrenia-like endophenotypes. PUBLIC HEALTH RELEVANCE: Schizophrenia is a severe, chronic mental illness with a lifetime prevalence of 0.12-1.6% worldwide. Most exciting have been recent associations of schizophrenia with specific genes, such as neuregulin1, however the exact mechanisms of this association are unclear. Our findings indicate that alterations in BACE1-dependent NRG1 signaling lead to schizophrenia-like phenotypes and implicate a novel molecular mechanism in the pathogenesis of schizophrenia and related psychiatric disorders. Given recent reports that impaired NRG1 signaling leads to glutamatergic hypofunction implicated in mechanisms of schizophrenia, we will test the hypothesis that BACE1-dependent impairments in NRG1 signaling modulate NMDA or AMPA receptors pathways. By using RNA interference and conditional BACE1 genetic models we will also analyze in what extent the expression of schizophrenia -like phenotypes depends on activity of BACE1 during development and in adulthood.