The major goals of the proposed research are 1) to investigate the role of the mu opioid receptor in long-term potentiation (LTP) at the hippocampal mossy fiber-CA3 synapse and in the acquisition of spatial memory, 2) to characterize the presumptive DNA recombinase which undergoes a mu opioid receptor-dependent upregulation during LTP and spatial learning, and 3) to investigate whether this presumptive recombinase is upregulated in other areas of the brain when other types of memory are acquired. Both long-term potentiation (LTP) at the hippocampal mossy fiber-CA3 synapse and the acquisition of spatial memory can be attenuated by a local blockade of mu opioid receptors. To confirm this pharmacological data, we will examine both these processes in mice that are genetically deficient in components of the mu opioid signaling system (receptor and ligand precursors). We predict that both processes will be impaired. We will extend our experiments to ascertain if other forms of hippocampal-dependent memory are impaired in these mice. Spatial learning or LTP at the mossy fiber-CA3 synapse both result in increased transcription of a presumptive DNA recombinase. In both cases, this upregulation can be clocked by mu opioid receptor antagonists. Long-term memories can involve permanent changes in gene expression, and somatic cell DNA recombination is capable of producing such changes. We will sequence the cDNA that encodes the presumptive DNA recombinase, and then confirm that increased transcription of this gene causes both increased enzymatic recombinase activity and concomitant DNA recombination in the intact animal. During spatial learning, increased transcription of the presumptive recombinase is not restricted to the mossy fiber-CA3 region, or even to the hippocampus. We will invoke different types of memory acquisition using different experimental protocols, and test if recombinase expression is increased in other regions (e.g. in the amygdala during fear conditioning). The proposed research therefore examines two topics of potential clinical significance: a memory-specific role of a receptor (the mu opioid receptor) known to be the target of some addictive drugs, and a candidate mechanism (the presumptive recombinase) for making the permanent cellular changes thought to underlie long-term memory.
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