mGluR2/3 influences in primate prefrontal cortex: potential for therapeutics

描述（由申请人提供）：拟议的研究将首次研究代谢性谷氨酸受体mGluR2/3对灵长类动物背外侧前额叶皮质（dlPFC）功能的影响，这是精神分裂症患者的一个大脑区域。II组代谢性谷氨酸受体（mGluR2、mGluR3）是潜在的治疗靶点，mGluR3的遗传改变与精神分裂症的关系越来越密切。然而，目前还没有关于这些受体如何影响灵长类动物dlPFC回路的研究，灵长类动物可能存在进化差异。本研究将确定mGluR2和mGluR3在灵长类动物dlPFC回路中的突触前和突触后位置，以及mGluR2/3刺激如何影响dlPFC神经元放电和认知功能。随着选择性mGluR2和mGluR3药物现在可用于研究，拟议的研究将开始分析mGluR2和mGluR3对神经元放电和认知表现的影响。初步数据显示，低剂量mGluR2/3激动剂可增强dlPFC神经元放电，改善猴子的工作记忆表现，且无明显副作用，具有临床应用潜力。目的1将使用多重标记，免疫电镜定位mGluR2和mGluR3在灵长类动物dlPFC突触前和突触后的位置。虽然啮齿类动物的研究主要集中在突触前定位，但灵长类动物dlPFC的初步数据表明，mGluR2/3也定位在突触后，靠近第三层兴奋性突触，定位于加强网络放电。将dlPFC的定位与眼眶PFC、颞叶皮层和初级视觉皮层的定位进行比较，看看dlPFC的定位模式是独特的，还是延伸到其他联想和/或感觉皮层。目的2将对执行空间工作记忆任务的猴子的dlPFC神经元进行单单元记录，以观察mGluR2/3信号的改变如何影响任务相关网络的激活。这些研究将能够观察药物治疗是减少神经元放电（与谷氨酸释放的突触前抑制一致），还是增加神经元放电（与cAMP-K+通道作用的突触后抑制一致）。混合mGluR2/3化合物的结果将与新获得的选择性mGluR2和mGluR3药物进行比较，以开始确定对dlPFC神经元放电的具体影响。初步数据表明，低剂量的mGluR2/3激动剂可大大增强维持工作记忆的dlPFC延迟细胞的放电。目标3将描述目标2中使用的化合物对猴子执行一系列认知任务的行为影响。初步数据表明，低剂量的mGlu2/3激动剂(2R,4R)-APDC可显著改善工作记忆表现，且几乎没有副作用，突出了这些机制的治疗潜力。拟议的实验将比较mGluR2/3化合物与选择性mGluR2和mGluR3药物的作用，以了解哪些受体是认知增强的基础。这些数据将为指导精神分裂症认知增强的治疗策略以及理解mGluR3的损伤如何影响认知功能提供重要信息。

DESCRIPTION (provided by applicant): The proposed research will provide the first study of metabotropic glutamate receptor mGluR2/3 influences on dorsolateral prefrontal cortex (dlPFC) function in primates, a brain region greatly afflicted in patients with schizophrenia. Group II metabotropic glutamate receptors (mGluR2, mGluR3) are potential therapeutic targets, and genetic alterations of mGluR3 are increasingly associated with schizophrenia. However, there has been no research on how these receptors influence dlPFC circuits in primates, where there are likely evolutionary differences. The proposed research will determine the pre- vs. post-synaptic location of mGluR2 vs. mGluR3 in primate dlPFC circuits, and how mGluR2/3 stimulation influences dlPFC neuronal firing and cognitive function. As selective mGluR2 and mGluR3 agents are now available for research use, the proposed research will begin to dissect mGluR2 vs. mGluR3 effects on neuronal firing and cognitive performance. Preliminary data show that low doses of an mGluR2/3 agonist can enhance dlPFC neuronal firing and improve working memory performance in monkeys, with no evident side effects, suggesting clinical potential. Aim 1 will use multiple label, immunoelectron microscopy to localize mGluR2 and mGluR3 in pre- vs. post-synaptic sites in the primate dlPFC. Although rodent studies have focused on pre-synaptic localization, preliminary data from primate dlPFC indicate that mGluR2/3 are also localized post-synaptically next to layer III excitatory synapses, positioned to strengthen network firing. Localization in dlPFC will be compared to that in orbital PFC, temporal cortex and primary visual cortex, to see if the pattern in dlPFC is unique, or extends to other association and/or sensory cortices. Aim 2 will perform single unit recording of dlPFC neurons in monkeys performing a spatial working memory task to observe how alterations in mGluR2/3 signaling influence task-related network firing. These studies will be able to observe whether a drug treatment decreases neuronal firing (consistent with pre- synaptic inhibition of glutamate release), or increases neuronal firing (consistent with post-synaptic inhibition of cAMP-K+ channel actions). Results with mixed mGluR2/3 compounds will be compared to newly available, selective mGluR2 and mGluR3 agents to begin to define specific influences on dlPFC neuronal firing. Preliminary data indicate that low doses of an mGluR2/3 agonist greatly enhance the firing of dlPFC Delay cells that maintain working memory. Aim 3 will characterize the behavioral effects of the compounds used in Aim 2, in monkeys performing a battery of cognitive tasks. Initial data indicate that low doses of the mGlu2/3 agonist, (2R,4R)-APDC, markedly improve working memory performance with few side effects, highlighting the therapeutic potential of these mechanisms. The proposed experiments will compare the effects of mGluR2/3 compounds to those of selective mGluR2 and mGluR3 agents to see which receptor(s) underlie the cognitive enhancement. These data will provide essential information for guiding therapeutic strategies for cognitive enhancement in schizophrenia, and for understanding how insults to mGluR3 can impact cognitive function.