| Literature DB >> 25937172 |
Jerri M Rook1, Zixiu Xiang1, Xiaohui Lv1, Ayan Ghoshal1, Jonathan W Dickerson1, Thomas M Bridges1, Kari A Johnson1, Daniel J Foster1, Karen J Gregory2, Paige N Vinson1, Analisa D Thompson1, Nellie Byun1, Rebekah L Collier1, Michael Bubser1, Michael T Nedelcovych1, Robert W Gould1, Shaun R Stauffer1, J Scott Daniels1, Colleen M Niswender1, Hilde Lavreysen3, Claire Mackie4, Susana Conde-Ceide5, Jesus Alcazar5, José M Bartolomé-Nebreda5, Gregor J Macdonald3, John C Talpos3, Thomas Steckler3, Carrie K Jones1, Craig W Lindsley1, P Jeffrey Conn6.
Abstract
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.Entities:
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Year: 2015 PMID： 25937172 PMCID： PMC4443790 DOI： 10.1016/j.neuron.2015.03.063
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173