Dopamine Modulation of NMDA Receptor Synaptic Responses

描述(由申请人提供)：因此，海马区多巴胺受体激活的效应可能为以显著相关的方式调节海马区依赖认知提供一种机制。本研究旨在探讨多巴胺D_1受体(包括D_1和D_5)激活对依赖NMDAR的海马区突触反应的影响及其机制。我们的初步研究结果表明，在CA1锥体神经元中，激活D1/5抑制了NMDAR对来自内嗅皮层的TamporoAmonic(TA)输入的突触反应，但在同一神经元上，激活D1/5则增强了NMDAR对来自CA3神经元的Schaeffer侧支(Sch)输入的突触反应。我们假设，这些相反的极性效应依赖于NMDAR亚基的组成和与不同亚基相关的细胞内信号机制。D_1/5效应的输入特异性反映了NMDAR亚单位组成的输入特异性。我们建议从NMDAR亚单位组成和细胞内信号机制方面来研究D1/5对CA1中NMDAR突触反应的作用。将结合细胞外和细胞内应用的试剂，使用体外培养的CA1神经元的全细胞电压钳记录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(使用不同于AMPAR依赖的LTP或LTD的机制)，我们建议在细胞内信号机制的水平上，对同一神经元上的两种输入中的每一种，研究活动依赖可塑性与D1/5诱导的NMDAR EPSCs变化的相互作用。最后，作为表征CA1NMDARs对海马依赖认知的D1/5调制的关键的第一步，我们将研究NMDARs在海马依赖的食欲和厌恶任务中在背侧CA1中的作用。NMDAR功能将被病毒载体介导的必要NR1亚基的局部基因缺失所破坏。然后，我们将使用病毒载体介导的干扰肽的定位表达，在体内检测干扰D1对NMDAR突触反应的调制对这些相同任务的获得的影响。这项研究多巴胺在调节髋关节顶叶功能中的作用的提议，将为包括药物滥用、抑郁和精神病在内的精神疾病提供新的见解，这些疾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.