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-Daspartate 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% 6 16% increase in cortical gamma-band oscillatory power in WT mice, but only a 15% 6 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.

The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function

“…One possibility is that the greater inhibition represents an early pathology and/or homeostatic mechanism to normalize cortical circuitry and requires further evaluation. Other groups have previously proposed a potential role of GluN2C/GluN2D subunits in schizophrenia154647. This notion emanates from the unique expression pattern of these subunits in interneuron subpopulations and in relevant thalamic nuclei8944.…”

Tonic Activation of GluN2C/GluN2D-Containing NMDA Receptors by Ambient Glutamate Facilitates Cortical Interneuron Maturation

“…Expression of these subunits in the cortex and hippocampus is largely restricted to GABAergic INs (Monyer et al, 1994;Xi et al, 2009). Accordingly, use-dependent NMDAR antagonists (blocking mostly extrasynaptic and nonsynaptic NMDARs) (Wu and Johnson, 2015;Sapkota et al, 2016) strongly affect cortical and hippocampal INs, leading to net disinhibition (Homayoun and Moghaddam, 2007;Riebe et al, 2016). In the current study, we demonstrate that cortical INs, but not L5Ps, are tonically depolarized by ambient glutamate acting at GluN2C/ DRs.…”

Convergent Mechanisms Underlying Rapid Antidepressant Action

“…However, there is also evidence that GluN2B-NMDAR inhibition increases gamma power specifically during rapid eye movement (REM) sleep state in rats, albeit at a lower magnitude compared with non-selective and GluN2A-NMDAR antagonists [156]. For ketamine, a critical role of GluN2D-NMDARs was reported to underlie the ability of the drug to induce high-frequency gamma oscillations, since this increase was absent in mice lacking the GluN2D gene [157]. …”