Dopamine Modulation of NMDA Receptor Synaptic Responses

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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.