Physiological Consequences of Glutamate Receptor Modulation

谷氨酸受体调节的生理后果

• 批准号: 0344559
• 负责人: Siqiong Liu
• 金额: $ 70.06万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0344559&HistoricalAwards=false
• 关键词: Physiological; Consequences; Glutamate; Receptor; Modulation

The long-term goal of this project is to reveal how neuronal activity produces a lasting change in synaptic transmission and subsequently alters the electrical signaling in a neuronal network. One fundamental feature of the central nervous system is that neuronal activity can modify the characteristics of the postsynaptic response. This use-dependent change in synaptic strength may alter information processing in a neuronal circuit and information storage within the brain. One of the proposed mechanisms for synaptic plasticity is that AMPA-type glutamate receptors present in the postsynaptic membrane undergo dynamic changes in response to alterations in synaptic activity. Alterations in the number of AMPA receptors and in their phosphorylation state can change the amplitude of the synaptic current and thereby alter the postsynaptic response. Recent work by Dr. Liu and her colleague has shown that the repetitive synaptic activation of a subset of AMPA receptors that are permeable to Ca2+ results in the rapid appearance of Ca2+-impermeable synaptic AMPA receptors in a cerebellar interneuron, the stellate cell. This switch not only reduces the amplitude of the synaptic current, but also prolongs the decay time course of the synaptic current. Interestingly, the reversal of this process, changing from Ca2+-impermeable to Ca2+-permeable AMPA receptors, occurs after epileptic seizures. This change may be involved in the pathogenesis of ischemia-induced neuronal death.With National Science Foundation support, Dr. Liu will study the physiological consequences of the activity-dependent switch in AMPA receptor subtypes. This investigation could further our understanding of how synaptic plasticity may alter input-output relationships within a cerebellar neuronal network that is essential for several forms of well characterized motor learning. This study may also increase our understanding of cellular mechanisms underlying neurological disorders associated with excessive activation of Ca2+-permeable AMPA receptors.

该项目的长期目标是揭示神经元活动如何产生突触传播的持久变化，并随后改变神经元网络中的电信号传导。中枢神经系统的一个基本特征是神经元活性可以改变突触后反应的特征。突触强度的这种使用依赖性变化可能会改变神经元电路中的信息处理和大脑内的信息存储。突触可塑性的提出机制之一是，突触后膜中存在的AMPA型谷氨酸受体会经历动态变化，以应对突触活动的改变。 AMPA受体及其磷酸化状态的变化可以改变突触电流的幅度，从而改变突触后反应。 Liu博士和她的同事的最新工作表明，AMPA受体子集的重复突触激活可渗透到Ca2+，从而导致Cerebellar Interneuron中Ca2+可耐受性突触AMPA受体的快速出现，即星状细胞。该开关不仅会降低突触电流的幅度，还可以延长突触电流的衰减时间过程。有趣的是，此过程的逆转从Ca2+易感到Ca2+可渗透的AMPA受体发生在癫痫发作后发生。这种变化可能与缺血诱导的神经元死亡的发病机理有关。刘博士将研究AMPA受体亚型的活动依赖性转换的生理后果。这项调查可以进一步了解突触可塑性如何改变小脑神经元网络中的输入输出关系，这对于几种表征良好的运动学习至关重要。这项研究还可能增加我们对与CA2+可渗透AMPA受体过度激活相关的神经系统疾病的细胞机制的理解。