Molecular mechanisms of long-term Depression in the hippocampus

海马长期抑郁的分子机制

• 批准号: MR/K023098/1
• 负责人: Graham Collingridge
• 金额: $ 247.28万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK023098%2F1
• 关键词: Molecular; mechanisms; long; term; Depression

Synaptic plasticity is the process by which synapses can alter their efficiency of transmission; the two main forms are long-term potentiation (LTP) and long-term depression (LTD). The principal excitatory neurotransmitter in the brain, L-glutamate, exerts its physiological actions via three types of ionotropic receptors, named after the agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate, as well as a family of G-protein coupled, metabotropic glutamate receptors (mGluRs). Since the discovery that NMDA receptors (NMDARs) are the trigger for LTP at CA1 synapses in the hippocampus, and that they are involved in hippocampus-dependent learning and memory, it has become very evident that NMDAR-dependent LTP (NMDAR-LTP) is critical for a variety of cognitive processes. More recently, evidence has been accumulating for the importance of LTD, triggered by the activation of NMDARs or mGluRs, in various forms of learning and memory. These plastic processes are critical throughout life, from the connections made during development through to explicit forms of learning and memory into adulthood. Increasingly it is being realised that alterations in LTP and LTD contribute in various ways to a variety of neurological and psychiatric disorders, such as dementia, epilepsy, depression and schizophrenia. We and others have recently made molecular links between plasticity and disease, which suggests that dysregulation in synaptic plasticity may directly contribute to the aetiology of a number of neurological pathologies. For example, in the process of studying mechanisms of LTD in the hippocampus, we have recently identified key roles for a number of proteins that are linked to neuropathogies, including glycogen synthase kinase-3beta (GSK-3beta). We now plan to address several key unanswered questions concerning molecular mechanisms of NMDAR-LTD and mGluR-LTD in the hippocampus, with a focus on phosphorylation cascades, Ca2+ signalling and glutamate receptor trafficking. Based on extensive pilot data we plan to establish new components of molecular pathways underlying different forms of LTD, and to deduce precisely how induction of LTD, and the accompanying transient increase in cytosolic Ca2+, results in alterations in the synaptic expression of glutamate receptors. A key new development for our work will be the study of LTD in adult mice in vivo. We plan to establish how the signalling cascades that have been identified in simplified preparations operate in the intact animal. These findings will contribute to a fuller understanding of the molecular basis of major forms of synaptic plasticity in the brain, work that is directly relevant to a substantial number of major brain disorders

突触可塑性是指突触可以改变其传递效率的过程；两种主要形式是长期增强（LTP）和长期抑制（LTD）。大脑中主要的兴奋性神经递质l-谷氨酸通过三种类型的离子性受体发挥其生理作用，这些受体分别以激动剂n -甲基- d -天冬氨酸（NMDA）、α -氨基-3-羟基-5-甲基-4-异唑丙酸（AMPA）和kainate命名，以及g蛋白偶联的代谢性谷氨酸受体（mGluRs）家族。自从发现NMDA受体（NMDARs）是海马体CA1突触LTP的触发器，并且它们参与海马体依赖性学习和记忆以来，NMDA依赖性LTP （NMDAR-LTP）对多种认知过程至关重要已经变得非常明显。最近，越来越多的证据表明，在各种形式的学习和记忆中，由NMDARs或mglur的激活引发的LTD的重要性。这些可塑过程在整个生命过程中都是至关重要的，从发育期间建立的联系，到成年后的学习和记忆的明确形式。越来越多的人认识到，LTP和LTD的改变以各种方式导致各种神经和精神疾病，如痴呆、癫痫、抑郁症和精神分裂症。我们和其他人最近在可塑性和疾病之间建立了分子联系，这表明突触可塑性的失调可能直接导致许多神经病理学的病因。例如，在研究海马LTD机制的过程中，我们最近发现了一些与神经病变相关的蛋白质的关键作用，包括糖原合成酶激酶-3 β (gsk -3 β)。我们现在计划解决关于NMDAR-LTD和mGluR-LTD在海马中的分子机制的几个关键未解问题，重点是磷酸化级联，Ca2+信号传导和谷氨酸受体运输。基于广泛的试点数据，我们计划建立不同形式LTD的分子通路的新组成部分，并精确推断LTD的诱导，以及伴随的胞质Ca2+的短暂增加，如何导致谷氨酸受体突触表达的改变。我们工作的一个关键的新发展将是在成年小鼠体内研究LTD。我们计划确定在简化制剂中发现的信号级联如何在完整动物中运作。这些发现将有助于更全面地了解大脑中突触可塑性主要形式的分子基础，这一工作与大量主要大脑疾病直接相关

项目成果

Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus.

• DOI: 10.1016/j.neuropharm.2016.08.010
• 发表时间: 2017-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: France G;Fernández-Fernández D;Burnell ES;Irvine MW;Monaghan DT;Jane DE;Bortolotto ZA;Collingridge GL;Volianskis A
• 通讯作者: Volianskis A

Differential regulation of STP, LTP and LTD by structurally diverse NMDA receptor subunit-specific positive allosteric modulators.

• DOI: 10.1016/j.neuropharm.2021.108840
• 发表时间: 2022-01-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: France G;Volianskis R;Ingram R;Bannister N;Rothärmel R;Irvine MW;Fang G;Burnell ES;Sapkota K;Costa BM;Chopra DA;Dravid SM;Michael-Titus AT;Monaghan DT;Georgiou J;Bortolotto ZA;Jane DE;Collingridge GL;Volianskis A
• 通讯作者: Volianskis A

GSK-3ß regulates the synaptic expression of NMDA receptors via phosphorylation of phosphatidylinositol 4 kinase type IIa

GSK-3 通过 IIa 型磷脂酰肌醇 4 激酶的磷酸化调节 NMDA 受体的突触表达

• DOI: 10.1101/841676
• 发表时间: 2019
• 作者: Amici M