GluN2D N-Methyl-d-Aspartate Receptor Subunit Contribution to the Stimulation of Brain Activity and Gamma Oscillations by Ketamine: Implications for Schizophrenia.

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.

NMDA receptors containing GluN2C and GluN2D subunits have opposing roles in modulating neuronal oscillations; potential mechanism for bidirectional feedback.

NMDA receptor (NMDAR) antagonists such as ketamine, can reproduce many of the symptoms of schizophrenia. A reliable indicator of NMDAR channel blocker action in vivo is the augmentation of neuronal oscillation power. Since the coordinated and rhythmic activation of neuronal assemblies (oscillations) is necessary for perception, cognition and working memory, their disruption (inappropriate augmentation or inhibition of oscillatory power or inter-regional coherence) both in psychiatric conditions and with NMDAR antagonists may reflect the underlying defects causing schizophrenia symptoms. NMDAR antagonists and knockout (KO) mice were used to evaluate the role of GluN2C and GluN2D NMDAR subunits in generating NMDAR antagonist-induced oscillations. We find that basal oscillatory power was elevated in GluN2C-KO mice, especially in the low gamma frequencies while there was no statistically significant difference in basal oscillations between WT and GluN2D-KO mice. Compared to wildtype (WT) mice, NMDAR channel blockers caused a greater increase in oscillatory power in GluN2C-KO mice and were relatively ineffective in inducing oscillations in GluN2D-KO mice. In contrast, preferential blockade of GluN2A- and GluN2B-containing receptors induced oscillations that did not appear to be changed in either KO animal. We propose a model wherein NMDARs containing GluN2C in astrocytes and GluN2D in interneurons serve to detect local cortical excitatory synaptic activity and provide excitatory and inhibitory feedback, respectively, to local populations of postsynaptic excitatory neurons and thereby bidirectionally modulate oscillatory power.