Molecular mechanisms of synapse development and plasticity

突触发育和可塑性的分子机制

• 批准号: 8342161
• 负责人: Zheng Li
• 金额: $ 61.93万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8342161
• 关键词: AMPA Receptors; Adverse event; Affect; Apoptosis; BAX gene; Brain; Caspase; Cell Death; Cell Differentiation process; Cells; Chronic; Cleaved cell; Cognition; Defect; Development; Disease; Electron Microscopy; Electrophysiology (science); Endocytosis; Environment; Etiology; Genes; Goals; Impaired cognition; Intervention; Knock-out; Knockout Mice; Knowledge; Long-Term Depression; Long-Term Potentiation; Maintenance; Measures; Mental disorders; Mitochondria; Modification; Molecular; Morphology; N-Methyl-D-Aspartate Receptors; Neurons; Pathology; Patients; Phenotype; Physiology; Prevention; Property; Schizophrenia; Signal Transduction; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; caspase-3; effective therapy; neural circuit; response; stem; synaptic function

By using gene knockdown and knockout mice, we demonstrated that the BAD-BAX-caspase-3 cascade is to induce NMDA receptor-dependent LTD and AMPA receptor endocytosis, but not for mGluR-LTD or long-term potentiation of synaptic transmission (Li et al., Cell 2010; Jiao et al., Neuron 2011). Unlike in apoptosis, however, BAD is activated only transiently and mildly leading to modest and transient caspase-3 activation insufficient to induce cell death. Our findings reveal a core signaling cascade for LTD induction and provide evidence that mechanistic and quantitative differences in caspase-3 activation are critical for determining whether it induces LTD or apoptosis. To determine if the BAD-BAX-caspase-3 cascade regulates other properties of synaptic transmission, we measured evoked and spontaneous excitatory synaptic response, and using electron microscopy to assess the ultrastructure of synapse in the knockout mice. To identify downstream effectors of the BAD-BAX-caspase-3 cascade that promotes LTD and AMPA receptor endocytosis, we collaborate with Dr. Sandy Markey to search for caspase substrates that are cleaved in LTD. We will use electrophysiology to determine if the identified caspase substrate is involved in LTD induction. We have previously collaborated with Dr. Richard Youle to examine the function of BAX in the maintenance of mitochondrial morphology (Norris et al., Cell Death and Differentiation 2010). Mitochondria morphology is important for mitochondria to support the development and function of synapses. To test whether the BAD-BAX-caspase-3 cascade regulates mitochondria morphology, we have examined mitochondria in BAD, BAX and caspase-3 knockout mice. We identified a fragmented mitochondrial phenotype and mitochondrial fusion defect in BAD and BAX knockout neurons. Therefore, we propose that BAD is an important activator of BAX for maintenance of mitochondria morphology in neurons.

通过使用基因敲低和基因敲除小鼠，我们证明了BAX-CASPASE-3级联反应是诱导NMDA受体依赖性LTD和AMPA受体内吞作用，但不是MGLUR-LTD或MGLUR-LTD或SNANTAPTIC的长期增强（Li et al。然而，与凋亡不同，BAD仅被瞬时和轻度激活，导致适度，瞬态caspase-3激活不足以诱导细胞死亡。我们的发现揭示了用于LTD诱导的核心信号传导级联，并提供了证据表明，Caspase-3激活中的机理和定量差异对于确定其诱导LTD还是凋亡至关重要。 为了确定不良型caspase-3级联反应是否调节突触传播的其他特性，我们测量了诱发和自发兴奋性突触反应，并使用电子显微镜评估敲除小鼠中突触的超微结构。为了鉴定促进LTD和AMPA受体内吞作用的不良Bax-Caspase-3级联反应的下游效应子，我们与Sandy Markey博士合作，搜索在LTD中切割的caspase底物。我们将使用电生理学来确定确定的caspase底物是否参与了LTD诱导。 我们以前曾与理查德·尤勒（Richard Youle）博士合作，研究了BAX在维持线粒体形态中的功能（Norris等人，Cell Death and Nictionation 2010）。线粒体形态对于线粒体支持突触的发展和功能很重要。为了测试不良的bax-caspase-3级联反应是否调节线粒体形态，我们检查了不良，BAX和caspase-3基因敲除小鼠的线粒体。我们确定了不良和BAX基因敲除神经元中的线粒体表型和线粒体融合缺陷。因此，我们认为BAD是维持神经元线粒体形态的BAX的重要激活因子。