Rook Jerri M, Xiang Zixiu, Lv Xiaohui, Ghoshal Ayan, Dickerson Jonathan W, Bridges Thomas M, Johnson Kari A, Foster Daniel J, Gregory Karen J, Vinson Paige N, Thompson Analisa D, Byun Nellie, Collier Rebekah L, Bubser Michael, Nedelcovych Michael T, Gould Robert W, Stauffer Shaun R, Daniels J Scott, Niswender Colleen M, Lavreysen Hilde, Mackie Claire, Conde-Ceide Susana, Alcazar Jesus, Bartolomé-Nebreda José M, Macdonald Gregor J, Talpos John C, Steckler Thomas, Jones Carrie K, Lindsley Craig W, Conn P Jeffrey
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA.
Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, TN 37232, USA; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
Neuron. 2015 May 20;86(4):1029-1040. doi: 10.1016/j.neuron.2015.03.063. Epub 2015 Apr 30.
Schizophrenia is associated with disruptions in N-methyl-D-aspartate glutamate receptor subtype (NMDAR)-mediated excitatory synaptic signaling. The metabotropic glutamate receptor subtype 5 (mGlu5) is a closely associated signaling partner with NMDARs and regulates NMDAR function in forebrain regions implicated in the pathology of schizophrenia. Efficacy of mGlu5 positive allosteric modulators (PAMs) in animal models of psychosis and cognition was previously attributed to potentiation of NMDAR function. To directly test this hypothesis, we identified VU0409551 as a novel mGlu5 PAM that exhibits distinct stimulus bias and selectively potentiates mGlu5 coupling to Gαq-mediated signaling but not mGlu5 modulation of NMDAR currents or NMDAR-dependent synaptic plasticity in the rat hippocampus. Interestingly, VU0409551 produced robust antipsychotic-like and cognition-enhancing activity in animal models. These data provide surprising new mechanistic insights into the actions of mGlu5 PAMs and suggest that modulation of NMDAR currents is not critical for in vivo efficacy. VIDEO ABSTRACT.
精神分裂症与N-甲基-D-天冬氨酸谷氨酸受体亚型（NMDAR）介导的兴奋性突触信号传导紊乱有关。代谢型谷氨酸受体亚型5（mGlu5）是与NMDAR密切相关的信号传导伙伴，并在前脑区域调节NMDAR功能，而这些区域与精神分裂症的病理机制有关。mGlu5正变构调节剂（PAM）在精神病和认知动物模型中的疗效以前被认为是由于NMDAR功能的增强。为了直接验证这一假设，我们确定VU0409551是一种新型mGlu5 PAM，它表现出独特的刺激偏向性，并且在大鼠海马体中选择性增强mGlu5与Gαq介导的信号传导的偶联，但不增强mGlu5对NMDAR电流或NMDAR依赖性突触可塑性的调节。有趣的是，VU0409551在动物模型中产生了强大的抗精神病样和认知增强活性。这些数据为mGlu5 PAM的作用提供了令人惊讶的新机制见解，并表明NMDAR电流的调节对体内疗效并不关键。视频摘要。
