Mechanisms of schizophrenia-like phenotypes in BACE 1 knockout mice

描述（由申请人提供）：位点APP裂解酶（BACE 1）裂解淀粉样前体蛋白（APP）作为淀粉样蛋白产生的初始步骤？（A？？）肽，这是参与阿尔茨海默病的发病机制。作为一种发育调节的乙酰基蛋白酶，BACE 1已被证明具有APP以外的推定底物，表明BACE 1的多种生理功能。最近，神经调节蛋白1（NRG 1）的BACE 1依赖性蛋白水解加工的变化与BACE 1-/-小鼠中中枢和外周髓鞘形成的缺陷有关。由于NRG 1也与精神分裂症有遗传联系，我们测试了NRG 1加工受损的BACE 1-/-小鼠是否表现出精神分裂症样行为异常。我们证明，BACE 1-/-小鼠表现出多种功能，被认为是精神分裂症症状的动物类似物，包括前脉冲抑制，新奇诱导的多动，超敏反应的一种mammatergic精神兴奋剂（MK-801），认知障碍和社会交往的改变赤字。重要的是，其中一些症状对氯氮平治疗有反应。ErbB 4的表达，NRG 1的受体和可能的NRG 1在大脑中的功能，特别是与精神分裂症相关的功能的主要介质，在BACE 1-/-小鼠中没有改变。然而，ErbB 4的突触池显著减少，如BACE-/-小鼠脑中ErbB 4和PSD-95的减少的关联所示。根据突触ErbB 4在突触功能和棘形态中的作用，BACE 1-/-小鼠显示海马锥体神经元棘密度降低。我们的研究结果表明，精神分裂症样内表型可以充分引起BACE 1的遗传缺陷，导致NRG 1/ErbB 4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机制的新机制。鉴于最近的报道，受损的NRG 1/ErbB 4信号转导导致精神分裂症的机制中牵连的多巴胺能功能减退，我们将测试NRG 1/ErbB 4信号转导中的BACE 1依赖性损伤可以调节NMDA或AMPA受体通路（Aim 1）的假设。在Aim 2中，我们将使用RNA干扰作为一种策略来研究发育期间或成年期启动的BACE 1抑制对成年小鼠精神分裂症样表型表达的影响。如果RNA干扰方法未能产生足够的BACE 1抑制，则将使用替代方法（在BACE 1空白背景下条件性表达BACE 1的小鼠模型）来调节不同发育阶段的BACE 1水平。拟议的研究将是重要的BACE 1相关的细胞通路和神经回路，参与精神分裂症样内表型的鉴定。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（如neuregulin 1）的关联，但这种关联的确切机制尚不清楚。我们的研究结果表明，BACE 1依赖性NRG 1信号的改变导致精神分裂症样表型，并涉及精神分裂症和相关精神疾病的发病机制中的一种新的分子机制。鉴于最近的报道，受损的NRG 1信号导致精神分裂症的机制中牵连的神经元功能减退，我们将测试NRG 1信号调节NMDA或AMPA受体通路的BACE 1依赖性损伤的假设。通过使用RNA干扰和条件BACE 1遗传模型，我们还将分析在发育期间和成年期，精神分裂症样表型的表达在多大程度上取决于BACE 1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.