MECHANISMS UNDERLYING ADRENAL STEROID MODULATION OF LTP

描述：肾上腺类固醇调节长时程增强（LTP）， 海马体 此外，两种类型的肾上腺类固醇受体， 盐皮质激素（MR）和糖皮质激素（GR）产生相反的作用 在齿状回（DG）和CA 1海马区-MR激活 增强而GR激活抑制LTP。 在CA 3领域，我们 观察到肾上腺皮质类固醇调节连合中的LTP/ 联想输入，LTP诱导需要激活N- 甲基-D-天冬氨酸受体（NMDAR），而对 苔藓纤维输入，LTP诱导是NMDAR独立的，但 而依赖于阿片肽。 这一发现表明， 肾上腺类固醇调节LTP的潜在机制。 急性应激也会抑制海马体中的LTP。 本来 应激引起的LTP抑制与血浆中 然而，后来的研究支持了这一假设 这些影响可能是由于阿片肽的升高， 而不是肾上腺类固醇 然而，由于一些原因，这些 调查结果是有争议的。 根据新的证据，包括 我们实验室的初步发现， 必须研究应激诱导的LTP抑制。 几乎没有什么是已知的，关于潜在的机制， LTP的肾上腺类固醇调节。 我们建议肾上腺 类固醇和压力调节海马体中的LTP（至少在某些情况下） 海马通路）通过其对海马能神经元的影响， 传输 这一假设得到了最近一些研究的支持。 发现：1）如上所述，在初步实验中我们发现 肾上腺皮质激素仅在已知LTP调节LTP的途径中调节LTP， 依赖于多巴胺能，NMDAR; 2）最近有报道 在压力期间阻断NMDAR可以消除压力 诱导抑制LTP; 3）我们现在有初步证据表明，MR 和GR激活通过NMDAR调节多巴胺能神经传递。 这一建议有三个部分：第一，初步 实验，测试MR和GR激活对LTP的影响， CA 3字段，将完成。 其次，我们将测试压力是否 诱导的LTP抑制也发生在NMDA依赖性和 阿片依赖性（NMDA非依赖性）途径最后， 肾上腺皮质类固醇和压力对NMDA依赖的神经传递将 被确定。 综合起来，这些实验的结果 应该提供第一个深入了解肾上腺皮质下的机制， 类固醇和应激诱导突触可塑性调节。 肾上腺 类固醇与学习和记忆、衰老和 老年痴呆症 了解其背后的机制 对突触可塑性的影响将大大增强我们对 它们如何与人类疾病有关。

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.