Regulation of glutamate receptors by calcium-dependent protein kinases

钙依赖性蛋白激酶对谷氨酸受体的调节

• 批准号: 10365955
• 负责人: Susumu Tomita
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10365955
• 关键词: AMPA Receptors; Animal Behavior; Animals; Automobile Driving; Behavior; Behavior Control; Binding; Biochemical; Brain; Cell membrane; Chemosensitization; Cognition Disorders; Cytoplasmic Tail; Dissociation; Glutamate Receptor; Goals; Health; Human; In Vitro; Knock-in Mouse; Laboratories; Learning; Long-Term Potentiation; Mediating; Memory; Mental Retardation; Mental disorders; Methods; Modeling; Molecular; Mutation; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Pathway interactions; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Positioning Attribute; Process; Property; Protein Dephosphorylation; Receptor Activation; Regulation; Role; Schizophrenia; Signal Transduction; Site; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Tweens; addiction; autism spectrum disorder; calcium-dependent protein kinase; calmodulin-dependent protein kinase II; conditioned fear; in vivo; insight; molecular drug target; neural circuit; neurotransmitter release; receptor; success

Neural circuits and their dynamic alteration control behavior. Neural circuits are composed of billions of neurons that communicate at synapses via the process of synaptic transmission, whereby neurotransmitters are released and bind to their respective receptors. Synaptic transmission can be persistently modified by neuronal activity in a process termed synaptic plasticity, acting to dynamically modulate animal behavior. Conversely, dysregulation of synaptic plasticity contributes to various psychiatric and cognitive disorders including autism, schizophrenia, mental retardation, and addiction. Therefore, proper synaptic plasticity is crucial for human health. Among various types of synaptic plasticity, NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) has been extensively studied. In this form of LTP, NMDAR activation increases synaptic AMPA receptor (AMPAR) activity through activation of CaMKII that drives AMPARs from a reserve pool to synapses. Though more than 100 molecules have been implicated in LTP, the direct cellular machinery remains unclear. Recently, we identified TARP-8 as a critical CaMKII substrate for LTP. In this propsal, we aim to reveal the fundamental mechanisms of AMPAR potentiation during synaptic plasticity. Successful completion of this proposal will provide fundamental mechanistic insights into LTP and its roles in controlling animal behavior. Considering synaptic plasticity as a general model to mediate dynamic brain function, elucidating the molecular mechanisms underlying the control of synaptic plasticity will enable us to identify putative molecular targets for drugs to alleviate psychiatric and cognitive disorders. Moreover, the identification of the critical molecules that control synaptic plasticity directly is a chief neurobiological goal.

神经回路及其动态变化控制行为。神经回路是 由数十亿个神经元组成，这些神经元通过突触过程进行交流 突触传递，其中神经递质被释放并结合到它们的 各自的受体。突触传递可以被神经元持续地改变， 在称为突触可塑性的过程中的活动，其作用是动态地调节动物的神经元， 行为相反，突触可塑性的失调有助于各种 精神和认知障碍，包括自闭症、精神分裂症、精神发育迟滞， 和上瘾。因此，适当的突触可塑性对人类健康至关重要。之间 各种类型的突触可塑性，NMDA受体（NMDAR）依赖的长期 增强作用（LTP）已被广泛研究。在这种形式的LTP中，NMDAR激活 通过激活CaMKII增加突触AMPA受体（AMPAR）活性， 将AMPAR从保留池驱动到突触。虽然超过100个分子 虽然LTP中涉及到了一些细胞机制，但直接的细胞机制仍不清楚。最近， 我们鉴定TARP β-8为LTP的关键CaMKII底物。在本提案中，我们的目标是 揭示了突触可塑性过程中AMPAR增强的基本机制。 成功完成此提案将提供基本的机械见解， LTP及其在动物行为控制中的作用将突触可塑性视为 介导动态脑功能的一般模型，阐明分子机制 突触可塑性控制的基础将使我们能够识别推定的分子 药物的目标，以减轻精神和认知障碍。而且 识别直接控制突触可塑性的关键分子是一个主要的 神经生物学目标