Long-Term Potentiation (LTP), is an enhancement of evoked neurotransmission which appears within minutes after brief, tetanic stimulation of an afferent, monosynaptic neural pathway and lasts from hours to weeks. LTP has been widely studied as a model of cellular information storage, and there is growing evidence implicating LTP-like mechanisms in memory processes. Three processes appear to be necessary for development of LTP: 1) postsynaptic depolarization, 2) activation of the voltage dependent glutamate receptor N-methyl-D-aspartate (NMDA), and 3) the influx of Ca++ into the postsynaptic terminal. However, some of the classic glutamatergic pathways in the rat hippocampal formation have been reported to contain opioid peptides. It has recently been demonstrated that opioid peptide release and/or opioid peptide receptor activation is necessary for LTP formation in these pathways. Taken together, opioid peptide regulation may be necessary for mechanisms associated with synaptic plasticity and learning. In the studies proposed, the dependence of lateral and medial perforant path-dentate gyrus LTP on opioid peptide receptors will be investigated using intra-hippocampal administration of either CTOP (mu-receptor specific antagonist), NTI (delta-receptor specific antagonist), nor-BNI (kappa-receptor specific antagonist) or the NMDA antagonists CPP. In addition, it is important to understand the relationship between opioid receptor activation and intracellular molecular events needed to induced potentiation. Understanding the cellular basis of LTP induction may elucidate molecular mechanism underlying long-term changes associated with memory formation. The expression of protooncogenes or immediate-early genes (IEG) can be induced in phasic electrophysiological events. The protein products of these IEG's work as nuclear transcription factors selectively regulating target genes associated with long-term alterations in cellular development and plasticity. Interestingly, high frequency stimulation of the mossy fibers in the hippocampus induces IEG activity in the dentate, and this expression is blocked by naloxone, which also blocks LTP induction. These data suggest IEG transcription and translocation may be a mechanism underlying opioid receptor dependent LTP maintenance.
Specific Aim 2 will examine whether expression of the IEG's c-fos, fra-1 and fos-b are associated with induction of LTP in either the literal and/or the medial perforant path-dentate gyrus LTP.
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