title: Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning.
abstract: Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5 signaling is required for different forms of adaptive learning. Here, we tested whether ADX47273, a selective positive allosteric modulator (PAM) of mGluR5, can enhance adaptive learning in mice. We found that systemic administration of the ADX47273 enhanced reversal learning in the Morris Water Maze, an adaptive task. In addition, we found that ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning. Together these results demonstrate a role for mGluR5 signaling in adaptive learning, and suggest that mGluR5 PAMs represent a viable strategy for treatment of maladaptive learning and for improving behavioral flexibility.
authors.affiliation: Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.forename: Yongling
authors.initials: Y
authors.lastname: Zhu
authors.forename: Stephen
authors.initials: S
authors.lastname: Kraniotis
authors.forename: Qionger
authors.initials: Q
authors.lastname: He
authors.forename: John J
authors.initials: JJ
authors.lastname: Marshall
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nomura
authors.forename: Shaun R
authors.initials: SR
authors.lastname: Stauffer
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Anis
authors.initials: A
authors.lastname: Contractor
mesh_terms: D000223:Adaptation, Psychological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010069:Oxadiazoles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects / Q000502:physiology*
chemical_list: D010069:Oxadiazoles; D010880:Piperidines; D064529:Receptor, Metabotropic Glutamate 5; C533862:S-(4-fluorophenyl)-(3-(3-(4-fluorophenyl)-(1,2,4)-oxadiazol-5-yl)piperidin-1-yl)methanone