AGRIN AND INTEGRIN EXPRESSION IN LEARNING AND LTP

由于在学习和长时程增强中观察到突触形态的变化，因此已知有助于突触接触稳定性的蛋白质对于理解记忆功能特别感兴趣。总体目标是研究在长时程增强和空间学习过程中聚集蛋白和整合素的mRNA表达，以及可能介导其在大鼠海马中表达的因素。聚集素和整合素是细胞外基质蛋白，可能在突触发生和现有突触的修饰中发挥重要作用。在学习和长时程增强中观察到形态学变化和/或突触发生。 初步研究发现，在学习空间导航任务期间，动物大脑中的mRNA表达再次被诱导。我们也有证据表明，聚集蛋白mRNA的表达与海马长时程增强。海马体显示至少两种形式的突触可塑性，需要激活多巴胺能受体的突触可塑性显示至少两种形式的突触可塑性，一种需要激活多巴胺能受体N-甲基-D-天冬氨酸（NMDA），另一种需要激活阿片受体。阿片样物质存在于通往CA 3区的外侧穿支通路、通往齿状回的外侧穿支通路和通往CA 3区的苔藓纤维中。因此，基因表达可通过NMDA和阿片受体的激活来调节。将使用清醒的自由移动大鼠在穿通通路-齿状回和穿通通路-CA 3通路中研究长期电位期间的聚集蛋白和整合素mRNA表达。这些通路表达NMDA和阿片受体依赖的长时程增强。具体目标1将调查时间mRNA表达的聚集蛋白和整合素在长时程增强。纳洛酮和选择性阿片或NMDA受体拮抗剂将用于研究阿片或NMDA受体的激活是否参与聚集蛋白或整联蛋白mRNA表达。具体目标2将研究Morris水迷宫任务的空间学习期间聚集蛋白的时程诱导。纳洛酮和选择性阿片受体和NMDA受体拮抗剂将用于研究阿片受体或NMDA受体的激活是否参与这种形式的学习过程中聚集蛋白或整联蛋白mRNA的表达。这些研究还将调查给予阿片类药物或NMDA受体拮抗剂时观察到的学习障碍是否与聚集蛋白和整联蛋白mRNA表达的阻断平行。

Since changes in synaptic morphology are observed in learning and long- term potentiation, proteins known to contribute to the stability of synaptic contacts are of particular interest to understand memory functions. The overall goal is to investigate mRNA expression of agrin and integrins, and the factors that may mediate their expression in the rat hippocampus during long-term potentiation and spatial learning. Agrins and integrins are extracellular matrix proteins that may play an important role in synaptogenesis and the modification of existing synapses. Both morphological changes and/or synaptogenesis have been observed in learning and long-term potentiation. Preliminary studies find that again mRNA expression is induced in the brain of animals during learning a spatial navigational task. We have evidence also that agrin mRNA is expressed with hippocampal long-term potentiation. The hippocampus displays t least two forms of synaptic plasticity, one that requires the activation of the glutaminergic receptor displays at least two forms of synaptic plasticity, one that requires the activation of the glutaminergic receptor N-Methyl-D-Aspartate (NMDA) and another that requires the activation of opiodergic receptors. Opioids are found in the lateral perforant path to area CA3, the lateral perforant path to dentate gyrus, and the mossy fiber to area CA3. Thus gene expression may be modulated by the activation of NMDA and opioid receptors. Agrin and integrin mRNA expression during long-term potential will be investigated in the perforant path-dentate gyrus and the perforant path-CA3 pathways using awake freely-moving rats. These pathways expressed NMDA and opioid- receptor dependent long-term potentiation. Specific Aim 1 will investigate temporal mRNA expression of agrin and integrins during long-term potentiation. Naloxone and selective opioid or NMDA receptor antagonists will be used to investigate if the activation of opioid or NMDA receptors is involved in agrin or integrins mRNA expression. Specific Aim 2 will investigate the time course induction of agrin during spatial learning of the Morris water maze task. Naloxone and selective opioid receptor and NMDA receptor antagonists will be used to investigate if the activation of opioid or NMDA receptors is involved in agrin or integrins mRNA expression during this form of learning. These studies will investigate also if the impairment in learning observed with the administration of opioid or NMDA receptor antagonists parallel the blockade of agrin and integrin mRNA expression.