Dopamine Modulation of NMDA Receptor Synaptic Responses

描述（由申请人提供）：海马中多巴胺受体激活的作用因此可以提供以显著性相关方式调节海马依赖性认知的机制。本研究拟探讨多巴胺D_1受体（包括D_1和D_5）激活对海马CA_1区NMDA受体（NMDAR）依赖性突触反应的影响及其作用机制。我们的初步研究结果表明，在CA 1锥体神经元，D1/5激活抑制NMDAR突触反应的TemporoAmonic（TA）输入从内嗅皮层，但在同一个神经元，D1/5激活增强NMDAR突触反应的Schaeffer侧支（Sch）输入从CA 3神经元。我们假设这些相反极性的影响是依赖于NMDAR亚基的组成和细胞内信号转导机制与不同的亚基。D1/5效应的输入特异性反映了NMDAR亚基组成的输入特异性。我们建议调查的D1/5行动NMDAR突触反应在CA 1的NMDAR亚基组成和细胞内信号机制。将使用体外CA 1神经元的全细胞电压钳记录以及细胞外和细胞内应用的试剂来评估对突触诱发的NMDAR反应的影响。由于NMDAR突触反应经历活动依赖的长期可塑性，导致LTP或LTD（使用的机制，是从AMPAR依赖的LTP或LTD不同），我们提出了一个检查的活动依赖的可塑性和D1/5诱导的NMDAR EPSC的变化在细胞内信号传导机制的水平，为同一神经元上的两个输入的相互作用。最后，作为一个关键的第一步，在表征的D1/5调制CA 1 NMDARs依赖于海马的认知，我们将研究NMDARs在背侧CA 1的作用，在海马依赖的食欲和厌恶的任务。将使用病毒载体介导的必需NR 1亚基的局灶基因缺失来破坏NMDAR功能。然后，我们将研究使用病毒载体介导的破坏肽的局部表达在体内破坏NMDAR突触反应的D1调制对获得这些相同任务的影响。这项研究多巴胺在调节海马功能中的作用的建议将为精神疾病提供新的见解，包括物质滥用，抑郁症和精神病，涉及奖励系统对认知的影响。

DESCRIPTION (provided by applicant): The effects of dopamine receptor activation in the hippocampus may thus, provide a mechanism for the modulation of hippocampal dependent cognition in a saliency related manner. This is a proposal to examine the effects and mechanism of action of dopamine D1 receptor (including D1 and D5) activation on NMDA receptor (NMDAR) dependent synaptic responses in the CA1 field of the hippocampus. Our preliminary findings show that in CA1 pyramidal neurons, D1/5 activation inhibits NMDAR synaptic responses to TemporoAmonic (TA) input from the entorhinal cortex, but, on the same neuron, D1/5 activation enhances NMDAR synaptic responses to Schaeffer Collateral (Sch) input from CA3 neurons. We hypothesize that these opposite polarity effects are dependent on NMDAR subunit composition and the intracellular signaling mechanisms associated with the different subunits. The input specificity of the D1/5 effects reflects the input specificity of the NMDAR subunit composition. We propose to investigate the D1/5 actions on NMDAR synaptic responses in CA1 with respect to the NMDAR subunit composition and intracellular signaling mechanisms. Effects on synaptically evoked NMDAR responses will be assessed using whole cell voltage clamp recordings of CA1 neurons in vitro in conjunction with extracellular and intracellularly applied reagents. Since NMDAR synaptic responses undergo activity dependent long term plasticity resulting in LTP or LTD (using mechanisms that are distinct from AMPAR-dependent LTP or LTD) we propose an examination of the interaction of activity dependent plasticity and D1/5 induced changes in NMDAR EPSCs at the level of intracellular signalling mechanisms, for each of the two inputs on the same neuron. Finally, as a critical first step in the characterization of a D1/5 modulation of CA1 NMDARs on hippocampal-dependent cognition, we will examine the role of NMDARs in the dorsal CA1, in a hippocampal dependent appetitive and aversive task. NMDAR function will be disrupted using a viral vector mediated focal gene deletion of the essential NR1 subunit. We will then examine the effect of disrupting D1 modulation of NMDAR synaptic responses in vivo using viral vector mediated localized expression of a disrupting peptide on the acquisition of these same tasks. This proposal to examine the role of dopamine in modulating hippocmapal function will provide new insights into psychiatric disorders including substance abuse, depression and psychosis that involve the reward system's influence on cognition.