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Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.


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 G?q-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.

SUBMITTER: Rook JM 

PROVIDER: S-EPMC4443790 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Biased mGlu5-Positive Allosteric Modulators Provide In Vivo Efficacy without Potentiating mGlu5 Modulation of NMDAR Currents.

Rook Jerri M JM   Xiang Zixiu Z   Lv Xiaohui X   Ghoshal Ayan A   Dickerson Jonathan W JW   Bridges Thomas M TM   Johnson Kari A KA   Foster Daniel J DJ   Gregory Karen J KJ   Vinson Paige N PN   Thompson Analisa D AD   Byun Nellie N   Collier Rebekah L RL   Bubser Michael M   Nedelcovych Michael T MT   Gould Robert W RW   Stauffer Shaun R SR   Daniels J Scott JS   Niswender Colleen M CM   Lavreysen Hilde H   Mackie Claire C   Conde-Ceide Susana S   Alcazar Jesus J   Bartolomé-Nebreda José M JM   Macdonald Gregor J GJ   Talpos John C JC   Steckler Thomas T   Jones Carrie K CK   Lindsley Craig W CW   Conn P Jeffrey PJ  

Neuron 20150430 4


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 f  ...[more]

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