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（由申请人提供）：拟议的研究将提供对代谢性谷氨酸受体MGLUR2/3的首次研究，对PRERATES背侧外侧前额叶皮层（DLPFC）功能的影响，这是一个大脑区域，这是一个在精神分裂症患者中大为折磨的大脑区域。 II组代谢型谷氨酸受体（MGLUR2，MGLUR3）是潜在的治疗靶标，MGLUR3的遗传改变与精神分裂症越来越多。但是，尚无关于这些受体如何影响灵长类动物中DLPFC电路的研究，在这种情况下可能存在进化差异。拟议的研究将确定灵长类动物DLPFC电路中MGLUR2与MGLUR3的前与突触后的位置，以及MGLUR2/3刺激如何影响DLPFC神经元的放电和认知功能。由于现在可以使用选择性MGLUR2和MGLUR3代理，因此拟议的研究将开始剖析MGLUR2与MGLUR3对神经元触发和认知性能的影响。初步数据表明，低剂量的MGLUR2/3激动剂可以增强DLPFC神经元的射击并改善猴子的工作记忆性能，没有明显的副作用，表明临床潜力。 AIM 1将使用多个标签，免疫电子显微镜将MGLUR2和MGLUR3定位在灵长类动物DLPFC中的Pre-Pre-Synaptic位点中。尽管啮齿动物的研究集中在突触前定位上，但来自灵长类动物DLPFC的初步数据表明，MGLUR2/3在III层兴奋性突触旁边也是局部突触后的局部化，该突触定位于增强网络射击。 DLPFC中的定位将与轨道PFC，颞皮层和主要视觉皮层中的定位进行比较，以查看DLPFC中的模式是唯一的，还是扩展到其他关联和/或感觉皮层。 AIM 2将执行执行空间工作记忆任务的猴子中DLPFC神经元的单个单位记录，以观察MGLUR2/3信号传导中的变化如何影响与任务相关的网络启动。这些研究将能够观察到药物治疗是降低神经元的发射（与突触前抑制谷氨酸释放一致），还是增加神经元的发射（与camp-K+通道作用的突触后抑制作用一致）。将混合MGLUR2/3化合物的结果与新获得的MGLUR2和MGLUR3剂进行比较，以开始定义对DLPFC神经元射击的特定影响。初步数据表明，低剂量的MGLUR2/3激动剂大大增强了维持工作记忆的DLPFC延迟细胞的发射。 AIM 3将表征AIM 2中使用的化合物的行为效应，在执行一系列认知任务的猴子中。初始数据表明，低剂量的MGLU2/3激动剂（2R，4R）-APDC显着改善了工作记忆性能，而副作用很少，从而突出了这些机制的治疗潜力。提出的实验将比较MGLUR2/3化合物与选择性MGLUR2和MGLUR3剂的作用，以查看哪种受体（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不可少的信息，并了解对MGLUR3的侮辱如何影响认知功能。