Potential mGluR treatment of age-related cognitive decline

描述(申请人提供)：这项拟议的研究将检验代谢性谷氨酸受体(MGluR)是否有潜力作为治疗年龄相关性认知障碍的治疗靶点。这项工作将揭示mGluR在进化的灵长类动物回路中的作用，这些回路有助于猴子和人类因正常衰老而受损的高级认知功能。药物的选择是由mGluR药理学世界专家杰弗里·康恩博士建议的。我们将研究mGluR2/3和mGluR5制剂如何影响年轻与老年猴子的前额叶皮质(PFC)生理学和认知。这项研究是及时的，因为mGluR5拮抗剂正在开发用于脆性X综合征，而mGluR2/3激动剂正在开发用于精神分裂症。因此，这些化合物可能在老年人中具有非标记性用途，以使老年PFC中的钙(Ca~(2+))和cAMP信号正常化。大量数据表明，老年PFC中的钙-cAMP信号增加，它通过开放PFC突触上钙和cAMP调节的K+通道来减少神经元的放电。MGluR5和mGluR2/3在灵长类PFC的高度进化的III层突触上定位于突触前和突触后。一般认为，mGluR5拮抗剂和mGluR2/3激动剂可以通过突触前抑制谷氨酸的释放来减轻兴奋性毒性。然而，这些药物也可能对灵长类PFC中的突触后受体有有益的作用，分别减少细胞内钙释放和抑制cAMP信号。目的1将研究混合mGluR2/3化合物(激动剂，(2R，4R)-APDC与拮抗剂LY341495)对幼猴和老年猴子的工作记忆和再认记忆表现，以及目的1B)PFC神经元放电的影响，以了解mGluR2/3激动剂是否有可能作为老年人的认知增强剂。目标2将开始使用新获得的、选择性的mGluR2和mGluR3化合物来剖析mGluR2和mGluR3在灵长类动物dlPFC中的作用，测试它们对目标A)认知能力和目标2B)神经元放电的影响。目的2C还将使用免疫电子显微镜(EM)来确定mGluR2和mGluR3在高度进化的灵长类皮质环路中突触前和突触后的位置，它们与PFC突触中的钙-cAMP-K+通道信号蛋白的相互作用，以及随着年龄的增长分布的任何变化。目标3将描述mGluR5在灵长类dlPFC中的作用。这些研究将考察选择性mGluR5激动剂VU0360172与选择性mGluR5拮抗剂Mtep或Fenobam对年轻和老年猴子的工作记忆和识别记忆能力以及目标3B(PFC神经元放电)的影响。目的利用免疫电子显微镜对mGluR5在幼年和老年灵长类动物皮质中的分布进行定位，以了解mGluR5是否与脊髓中的钙-cAMP-K+通道信号蛋白共定位，以及这些受体在突触前后的分布是否有年龄相关性的变化。初步数据显示，低剂量的混合mGluR2/3激动剂APDC或mGluR5拮抗剂MTEP可以改善老年猴子的认知能力，增强神经元放电，这与潜在的治疗作用一致。

DESCRIPTION (provided by applicant): The proposed research will examine whether metabotropic glutamate receptors (mGluR) have potential as therapeutic targets for treating age-related cognitive decline. The work will reveal mGluR actions in the evolved primate circuits that subserve the higher cognitive functions impaired by normal aging in monkeys and humans. The choice of drugs was advised by Dr. Jeffrey Conn, a world expert in mGluR pharmacology. We will examine how mGluR2/3 and mGluR5 agents influence prefrontal cortical (PFC) physiology and cognition in young vs. aged monkeys. This research is timely, as mGluR5 antagonists are being developed for Fragile X Syndrome, while mGluR2/3 agonists are being developed for schizophrenia. Thus, these compounds may have off-label use in the elderly to normalize calcium (Ca2+) and cAMP signaling in the aged PFC. A variety of data have shown evidence of increased Ca2+-cAMP signaling in the aged PFC, which reduces neuronal firing by opening Ca2+- and cAMP-regulated K+ channels on PFC synapses. mGluR5 and mGluR2/3 are localized both pre- and post-synaptically on highly evolved, layer III synapses in primate PFC. It is generally appreciated that mGluR5 antagonists and mGluR2/3 agonists can decrease excitotoxicity by pre-synaptic inhibition of glutamate release. However, these agents may also have beneficial actions at post-synaptic receptors in the primate PFC, reducing intracellular Ca2+ release and inhibiting cAMP signaling, respectively. Aim 1 will characterize the effects of mixed mGluR2/3 compounds (the agonist, (2R,4R)-APDC vs antagonist, LY341495) on Aim 1A) working memory and recognition memory performance, and Aim 1B) PFC neuronal firing, in young vs. aged monkeys to see if mGluR2/3 agonists may have potential as cognitive enhancers for the elderly. Aim 2 will begin to dissect mGluR2 vs. mGluR3 actions in primate dlPFC using newly available, selective mGluR2 vs. mGluR3 compounds, examining their effects on Aim 2A) cognitive performance and Aim 2B) neuronal firing. Aim 2C will also use immunoelectron microscopy (EM) to determine the pre- vs. post- synaptic location of mGluR2 vs. mGluR3 in highly evolved primate cortical circuits, their interactions with Ca2+- cAMP-K+ channel signaling proteins in PFC synapses, and any changes in distribution with advancing age. Aim 3 will characterize mGluR5 actions in primate dlPFC. These studies will examine the effects of the selective mGluR5 agonist, VU0360172, vs. the selective mGluR5 antagonists, MTEP or fenobam, on: Aim 3A) working memory and recognition memory abilities, and Aim 3B, PFC neuronal firing, in young and aged monkeys. Aim 3C will use immunoEM to localize mGluR5 in the young vs. aged primate cortex to see if mGluR5 co-localize with Ca2+-cAMP- K+ channel signaling proteins in spines, and whether there are any age- related changes in the pre- vs. post-synaptic distribution of these receptors. Preliminary data show improved cognitive performance and enhanced neuronal firing with low doses of the mixed mGluR2/3 agonist, APDC, or the mGluR5 antagonist, MTEP, in aged monkeys, consistent with potential therapeutic actions.