Potential mGluR treatment of age-related cognitive decline

描述（由申请人提供）：拟议的研究将检查代谢型谷氨酸受体（mGluR）是否有潜力作为治疗年龄相关性认知衰退的治疗靶点。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。药物的选择由mGluR药理学世界专家Jeffrey Conn博士提供建议。我们将研究mGluR 2/3和mGluR 5药物如何影响年轻与老年猴子的前额叶皮层（PFC）生理学和认知。这项研究是及时的，因为mGluR 5拮抗剂正在开发用于脆性X综合征，而mGluR 2/3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标签外使用，以使老年PFC中的钙（Ca 2+）和cAMP信号正常化。各种数据已经显示出老年PFC中Ca 2 +-cAMP信号增加的证据，其通过打开PFC突触上的Ca 2+和cAMP调节的K+通道来减少神经元放电。mGluR 5和mGluR 2/3位于灵长类PFC中高度进化的第III层突触的突触前和突触后。通常理解，mGluR 5拮抗剂和mGluR 2/3激动剂可以通过突触前抑制谷氨酸释放来降低兴奋性毒性。然而，这些药物也可能对灵长类PFC中的突触后受体具有有益作用，分别减少细胞内Ca 2+释放和抑制cAMP信号传导。目的1将表征混合mGluR 2/3化合物（激动剂，（2 R，4 R）-APDC vs拮抗剂，LY 341495）对年轻与老年猴中Aim 1A）工作记忆和识别记忆表现以及Aim 1B）PFC神经元放电的影响，以观察mGluR 2/3激动剂是否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mGluR 2与mGluR 3化合物来剖析灵长类动物dlPFC中mGluR 2与mGluR 3的作用，检查它们对目标2A）认知表现和目标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mGluR 2与mGluR 3在高度进化的灵长类动物皮层回路中的突触前与突触后位置、它们与PFC突触中的Ca 2 +-cAMP-K+通道信号传导蛋白的相互作用以及随着年龄增长分布的任何变化。目的3将表征mGluR 5在灵长类dlPFC中的作用。这些研究将检查选择性mGluR 5激动剂VU 0360172与选择性mGluR 5拮抗剂MTEP或非诺班对年轻和老年猴的Aim 3A）工作记忆和识别记忆能力以及Aim 3B PFC神经元放电的影响。目的3C将使用免疫电镜定位年轻与老年灵长类动物皮层中的mGluR 5，以观察mGluR 5是否与棘中的Ca 2 +-cAMP- K+通道信号传导蛋白共定位，以及这些受体的突触前与突触后分布是否存在任何年龄相关的变化。初步数据显示，在老年猴中，低剂量的混合mGluR 2/3激动剂APDC或mGluR 5拮抗剂MTEP改善了认知性能并增强了神经元放电，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.