GluN2D N-methyl-D-aspartate receptor subunit contribution to the stimulation of brain activity and gamma oscillations by ketamine: Implications for schizophrenia

Kiran Sapkota, Zhihao Mao, Paul Synowicki, Dillon Lieber, Meng Liu, Tsuneya Ikezu, Vivek Gautam, Daniel T. Monaghan

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 (GluN2DKO) mice. In WT mice, ketamine (30 mg/kg, i.p.) significantly increased [14C]-2-deoxyglucose ([14C]-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 [14C]-2DG uptake in any brain region examined, yet still decreased [14C]-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.

Original languageEnglish (US)
Pages (from-to)702-711
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume356
Issue number3
DOIs
StatePublished - Mar 1 2016

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Ketamine
N-Methyl-D-Aspartate Receptors
Schizophrenia
Brain
Inferior Colliculi
Somatosensory Cortex
Dissociative Anesthetics
Parvalbumins
Entorhinal Cortex
Aptitude
Deoxyglucose
Locomotion
Prefrontal Cortex
Knockout Mice
Cognition
Nervous System
Staining and Labeling

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

GluN2D N-methyl-D-aspartate receptor subunit contribution to the stimulation of brain activity and gamma oscillations by ketamine : Implications for schizophrenia. / Sapkota, Kiran; Mao, Zhihao; Synowicki, Paul; Lieber, Dillon; Liu, Meng; Ikezu, Tsuneya; Gautam, Vivek; Monaghan, Daniel T.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 356, No. 3, 01.03.2016, p. 702-711.

Research output: Contribution to journalArticle

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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 (GluN2DKO) mice. In WT mice, ketamine (30 mg/kg, i.p.) significantly increased [14C]-2-deoxyglucose ([14C]-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 [14C]-2DG uptake in any brain region examined, yet still decreased [14C]-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.",
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