title: Increased Metabotropic Glutamate Receptor 5 Signaling Underlies Obsessive-Compulsive Disorder-like Behavioral and Striatal Circuit Abnormalities in Mice.
abstract: Development of treatments for obsessive-compulsive disorder (OCD) is hampered by a lack of mechanistic understanding about this prevalent neuropsychiatric condition. Although circuit changes such as elevated frontostriatal activity are linked to OCD, the underlying molecular signaling that drives OCD-related behaviors remains largely unknown. Here, we examine the significance of type 5 metabotropic glutamate receptors (mGluR5s) for behavioral and circuit abnormalities relevant to OCD.
  
  
  
  Sapap3 knockout (KO) mice treated acutely with an mGluR5 antagonist were evaluated for OCD-relevant phenotypes of self-grooming, anxiety-like behaviors, and increased striatal activity. The role of mGluR5 in the striatal circuit abnormalities of Sapap3 KO mice was further explored using two-photon calcium imaging to monitor striatal output from the direct and indirect pathways. A contribution of constitutive signaling to increased striatal mGluR5 activity in Sapap3 KO mice was investigated using pharmacologic and biochemical approaches. Finally, sufficiency of mGluR5 to drive OCD-like behavior in wild-type mice was tested by potentiating mGluR5 with a positive allosteric modulator.
  
  
  
  Excessive mGluR5 signaling underlies OCD-like behaviors and striatal circuit abnormalities in Sapap3 KO mice. Accordingly, enhancing mGluR5 activity acutely recapitulates these behavioral phenotypes in wild-type mice. In Sapap3 KO mice, elevated mGluR5 signaling is associated with constitutively active receptors and increased and imbalanced striatal output that is acutely corrected by antagonizing striatal mGluR5.
  
  
  
  These findings demonstrate a causal role for increased mGluR5 signaling in driving striatal output abnormalities and behaviors with relevance to OCD and show the tractability of acute mGluR5 inhibition to remedy circuit and behavioral abnormalities.
authors.affiliation: Departments of Neurology, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Ade
authors.affiliation: Departments of Neurology, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Yehong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Departments of Neurology, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Harold C
authors.initials: HC
authors.lastname: Hamann
authors.affiliation: Departments of Neurology, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Justin K
authors.initials: JK
authors.lastname: O'Hare
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Weirui
authors.initials: W
authors.lastname: Guo
authors.affiliation: Departments of Neurology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Anna
authors.initials: A
authors.lastname: Quian
authors.affiliation: Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Departments of Neurology, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Srishti
authors.initials: S
authors.lastname: Bhagat
authors.affiliation: Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.affiliation: Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.affiliation: Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Kafui
authors.initials: K
authors.lastname: Dzirasa
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
authors.affiliation: Departments of Neurology, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina. Electronic address: nicole.calakos@duke.edu.
authors.forename: Nicole
authors.initials: N
authors.lastname: Calakos
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006120:Grooming / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009771:Obsessive-Compulsive Disorder / Q000503:physiopathology*; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5 / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; C581972:N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide; D009419:Nerve Tissue Proteins; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; C523020:Sapap3 protein, mouse; D013844:Thiazoles; C474696:methyl-(4-carboxyphenyl)glycine; D009536:Niacinamide; D005998:Glycine
keywords: Circuit; Constitutive activity; Obsessive-compulsive disorder; Positive allosteric modulator; Striatum; mGluR5