MECHANISMS UNDERLYING ADRENAL STEROID MODULATION OF LTP

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DESCRIPTION: Adrenal steroids modulate long-term potentiation (LTP) in the hippocampus. Further, the two types of adrenal steroid receptors, mineralocorticoid (MR) and glucocorticoid (GR), produce opposite effects in th dentate gyrus (DG) and CA1 hippocampal field-MR activation enhances while GR activation suppresses LTP. In the CA3 field, we observed that adrenal steroids modulate LTP in the commissural/ association input, for which LTP induction requires activation of N- methyl-D-aspartate receptors (NMDAR), while having no effects on the mossy fiber input for which LTP induction is NMDAR-independent, but rather depends on opioid peptides. This finding suggests possible underlying mechanisms for the adrenal steroid modulation of LTP. Acute stress also suppresses LTP in the hippocampus. Originally, the stress induced suppression in LTP was correlated with elevated plasma corticosterone levels, however, later studies supported the hypothesis that these effects wer probably due to elevations in opioid peptides, rather than adrenal steroids. For a number of reasons, however, these findings, are controversial. In light of new evidence, including preliminary findings from our laboratory, the mechanisms underlying stress induced suppression of LTP will have to be investigated. Practically nothing is known, about the mechanisms underlying the adrenal steroid modulation of LTP. We propose that both adrenal steroids and stress modulate LTP in the hippocampus (at least in certain hippocampal pathways) through their effects on glutamatergic neuro- transmission. This hypothesis is supported by a number of recent findings: 1) As stated above, in preliminary experiments we found that adrenal steroids modulate LTP only in pathways in which LTP is known to be dependent on glutamatergic, NMDAR; 2) it has been reported recently that blockade of NMDAR during the stress period eliminates the stress- induced suppression in LTP; 3) we now have preliminary evidence tha MR and GR activation modulate glutamatergic neurotransmission via NMDAR. There are three parts to this proposal: first, the preliminary experiments, testing the effects of MR and GR activation on LTP in the CA3 field, will be completed. Second, we will test whether stress induced suppression in LTP also occurs in both NMDA-dependent and opioid-dependent (NMDA-independent) pathways Finally, the direct effects of adrenal steroids and stress on NMDA dependent neurotransmission will be determined. Taken together, the results from these experiments should provide the first insight of the mechanisms underlying adrenal steroid and stress induced modulation of synaptic plasticity. Adrenal steroids have been implicated in learning and memory, aging and Alzheimer's disease. Understanding the mechanisms underlying their effects on synaptic plasticity will greatly enhance out understanding of how they may be involved in human disease.