Signal Convergence in Striatal Synaptic Plasticity

纹状体突触可塑性的信号收敛

• 批准号: 7057585
• 负责人: David S Tukey
• 金额: $ 3.19万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7057585
• 关键词: AMPA receptors; NMDA receptors; biological signal transduction; cAMP response element binding protein; corpus striatum; cyclic GMP; dopamine receptor; enzyme activity; green fluorescent proteins; laboratory rat; long term potentiation; memory; mitogen activated protein kinase; neural plasticity; neural transmission; neuropsychology; nitric oxide synthase; phosphorylation; predoctoral investigator; protein kinase; protein transport; synapses; tissue /cell culture; voltage /patch clamp

DESCRIPTION (provided by applicant): Synaptic plasticity induced by convergent dopaminergic and glutamatergic striatal afferents is a substrate for emotional memory in the brain. We have found that activation of both NMDA-type glutamate receptors and dopamine D1 receptors induces phosphorylation of neuronal nitric oxide synthase (nNOS) at its putative activation site, Ser 1412, and increases accumulation of cyclic GMP (cGMP). The mechanism of D1R activation of the nNOS pathway will be investigated, focusing on the role of Akt in phosphorylation of nNOS. Ramifications for D1R/NMDAR activation of CREB and ERK, proteins important for long-term synaptic plasticity, will be investigated and the role of cGMP in activity changes determined. Assays for changes in surface expression of the AMPA receptor subunit GluR1 in response to D1R and NMDAR-induced cGMP accumulation will be performed. Patch clamp recordings will be performed on cultured striatal neurons, and the effects of D1 R/NMDAR convergence at nNOS in potentiation of mEPSCs will be determined. We hypothesize that activation of nNOS by D1 R/NMDAR stimulation is important for rapidly potentiating synapses by increasing the rate of trafficking of calcium-permeable AMPA receptors to the membrane.

描述（由申请人提供）：由融合多巴胺能和谷氨酸能纹状体传入引起的突触可塑性是大脑情绪记忆的底物。我们发现，NMDA型谷氨酸受体和多巴胺D1受体的激活诱导神经元一氮氧化物合酶（NNOS）在其推定的激活位点的磷酸化，SER 1412，并增加了环状GMP（CGMP）的积累。 NNOS途径的D1R激活机制将进行研究，重点是AKT在NNOS磷酸化中的作用。将研究CREB和ERK的D1R/NMDAR激活的后果，对长期突触可塑性很重要的蛋白质，并研究CGMP在确定活性变化中的作用。将对D1R和NMDAR诱导的CGMP积累的AMPA受体亚基GLUR1的表面表达变化的分析进行测定。贴片夹记录将对培养的纹状体神经元进行，并确定D1 R/NMDAR收敛在NNOS对MEPSC增强中的影响。我们假设D1 R/NMDAR刺激对NNO的激活对于通过增加钙可渗透AMPA受体的运输速率来快速增强突触很重要。