title: GluN2D N-Methyl-d-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia.
abstract: The dissociative anesthetic ketamine elicits symptoms of schizophrenia at subanesthetic doses by blocking N-methyl-d-aspartate receptors (NMDARs). This property led to a variety of studies resulting in the now well-supported theory that hypofunction of NMDARs is responsible for many of the symptoms of schizophrenia. However, the roles played by specific NMDAR subunits in different symptom components are unknown. To evaluate the potential contribution of GluN2D NMDAR subunits to antagonist-induced cortical activation and schizophrenia symptoms, we determined the ability of ketamine to alter regional brain activity and gamma frequency band neuronal oscillations in wild-type (WT) and GluN2D-knockout (GluN2D-KO) mice. In WT mice, ketamine (30 mg/kg, i.p.) significantly increased [(14)C]-2-deoxyglucose ([(14)C]-2DG) uptake in the medial prefrontal cortex (mPFC), entorhinal cortex and other brain regions, and decreased activity in the somatosensory cortex and inferior colliculus. In GluN2D-KO mice, however, ketamine did not significantly increase [(14)C]-2DG uptake in any brain region examined, yet still decreased [(14)C]-2DG uptake in the somatosensory cortex and inferior colliculus. Ketamine also increased locomotor activity in WT mice but not in GluN2D-KO mice. In electrocorticographic analysis, ketamine induced a 111% ± 16% increase in cortical gamma-band oscillatory power in WT mice, but only a 15% ± 12% increase in GluN2D-KO mice. Consistent with GluN2D involvement in schizophrenia-related neurologic changes, GluN2D-KO mice displayed impaired spatial memory acquisition and reduced parvalbumin (PV)-immunopositive staining compared with control mice. These results suggest a critical role of GluN2D-containing NMDARs in neuronal oscillations and ketamine's psychotomimetic, dissociative effects and hence suggests a critical role for GluN2D subunits in cognition and perception.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.).
authors.forename: Kiran
authors.identifier: http://orcid.org/0000-0003-3737-2900
authors.initials: K
authors.lastname: Sapkota
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.).
authors.forename: Zhihao
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.).
authors.forename: Paul
authors.initials: P
authors.lastname: Synowicki
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.).
authors.forename: Dillon
authors.initials: D
authors.lastname: Lieber
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.).
authors.forename: Meng
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.).
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.).
authors.forename: Vivek
authors.initials: V
authors.lastname: Gautam
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska (K.S., Z.M., P.S., D.L., M.L., D.T.M.); Departments of Pharmacology & Experimental Therapeutics and Neurology, School of Medicine, Boston University, Boston, Massachusetts (T.I.); Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (V.G.) dtmonagh@unmc.edu.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Monaghan
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists; D065818:Gamma Rhythm / Q000187:drug effects / Q000502:physiology*; D007649:Ketamine / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; C464436:NR2D NMDA receptor; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine