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

mGluR2/3 对灵长类前额皮质的影响：治疗潜力

• 批准号: 8630805
• 负责人: AMY F.T. ARNSTEN
• 金额: $ 49.95万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-20 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630805
• 关键词: Adverse effects; Agonist; Area; Behavioral; Behavioral inhibition; Brain region; Cells; Clinical; Cognition; Cognitive; Cognitive deficits; Cyclic AMP; Data; Dendritic Spines; Development; Discrimination; Disease; Dose; Excitatory Synapse; Family; Genetic; Glutamates; Health; Human; Immunoelectron Microscopy; Independent Living; Industry; Injection of therapeutic agent; Iontophoresis; Label; Link; Location; Mediating; Metabotropic Glutamate Receptors; Methods; Monkeys; Mutation; N-Methylaspartate; Neuroglia; Neurons; Patients; Pattern; Performance; Pharmaceutical Preparations; Physiology; Positioning Attribute; Potassium Channel; Prefrontal Cortex; Primates; Production; Research; Rodent; Role; Saccades; Schizophrenia; Short-Term Memory; Signal Transduction; Site; Synapses; Task Performances; Temporal Lobe; Testing; Therapeutic; Work; area striata; association cortex; cognitive enhancement; cognitive function; density; drug development; effective therapy; flexibility; improved; interest; memory recognition; metabotropic glutamate receptor 2; metabotropic glutamate receptor 3; neuropsychiatry; postsynaptic; presynaptic; prevent; receptor; research study; response; restoration; sensory cortex; synaptic inhibition; therapeutic target; transmission process

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.

描述(申请人提供)：这项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严重困扰的大脑区域。第二组代谢性谷氨酸受体(mGluR2、mGluR3)是潜在的治疗靶点，mGluR3的基因改变与精神分裂症的相关性越来越大。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，在灵长类动物中，可能存在进化差异。这项拟议的研究将确定mGluR2和mGluR3在灵长类dlPFC回路中突触前和突触后的位置，以及刺激mGluR2/3如何影响dlPFC神经元的放电和认知功能。随着选择性mGluR2和mGluR3药物现在可用于研究用途，拟议的研究将开始剖析mGluR2和mGluR3对神经元放电和认知能力的影响。初步数据显示，低剂量的mGluR2/3激动剂可以增强dlPFC神经元的放电，改善猴子的工作记忆成绩，没有明显的副作用，提示临床潜力。目的1利用多重标记免疫电子显微镜对灵长类dlPFC突触前和突触后的mGluR2和mGluR3进行定位。虽然啮齿动物的研究主要集中在突触前定位，但来自灵长类动物dlPFC的初步数据表明，mGluR2/3也定位于突触后，紧邻第三层兴奋性突触，定位于加强网络放电。DlPFC的定位将与眶PFC、颞叶皮质和初级视皮层的定位进行比较，以了解dlPFC的模式是否独一无二，或者是否延伸到其他联系和/或感觉皮质。Aim 2将对执行空间工作记忆任务的猴子的dlPFC神经元进行单单位记录，以观察mGluR2/3信号的变化如何影响与任务相关的网络放电。这些研究将能够观察药物治疗是减少神经元放电(与突触前抑制谷氨酸释放一致)，还是增加神经元放电(与突触后抑制cAMP-K+通道作用一致)。使用混合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神经元放电的特定影响。初步数据表明，低剂量的mGluR2/3激动剂极大地增强了维持工作记忆的dlPFC延迟细胞的激发。目标3将描述目标2中使用的化合物在执行一系列认知任务的猴子身上的行为影响。初步数据表明，低剂量的mGlu2/3激动剂(2R，4R)-APDC显著改善工作记忆成绩，副作用很少，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药物的效果，以了解哪种受体(S)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提供必要的信息，并了解对mGluR3的侮辱如何影响认知功能。