Dopamine Modulation of NMDA Receptor Synaptic Responses

描述（由申请人提供）：因此，海马体中多巴胺受体激活的影响可能以显著性相关的方式为海马体依赖性认知的调节提供了一种机制。本研究旨在探讨多巴胺D1受体（包括D1和D5）激活对海马CA1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CA1锥体神经元中，D1/5的激活抑制了NMDAR突触对来自内嗅皮层的颞空（TA）输入的反应，但在同一神经元上，D1/5的激活增强了NMDAR突触对来自CA3神经元的谢弗侧枝（Schaeffer Collateral）输入的反应。我们假设这些相反的极性效应依赖于NMDAR亚基组成和与不同亚基相关的细胞内信号传导机制。D1/5效应的输入特异性反映了NMDAR亚基组成的输入特异性。我们拟从NMDAR亚基组成和细胞内信号机制方面研究D1/5对CA1中NMDAR突触反应的作用。利用体外CA1神经元的全细胞电压钳记录，结合细胞外和细胞内应用试剂，评估突触诱发的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水平上检查活动依赖的可塑性和D1/5诱导的NMDAR EPSCs变化的相互作用，对于同一神经元上的两个输入中的每一个。最后，作为表征CA1 NMDARs对海马依赖性认知的D1/5调节的关键第一步，我们将研究NMDARs在海马依赖性食欲和厌恶任务中CA1背侧的作用。NMDAR功能将通过病毒载体介导的NR1亚基的局灶性基因缺失而中断。然后，我们将使用病毒载体介导的干扰肽的局部表达来研究体内干扰D1对NMDAR突触反应的调节对这些相同任务的获得的影响。这一研究多巴胺在调节海马功能中的作用的建议将为涉及奖励系统对认知影响的精神疾病，包括药物滥用、抑郁和精神病提供新的见解。

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.