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

Abstract

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

Distinct structure and gating mechanism in diverse NMDA receptors with GluN2C and GluN2D subunits

“…At the cellular level, N2C is predominately expressed in cerebellar granule cells 18, 19 , and both N2C and N2D are enriched in the GABAergic interneurons 20, 21 . Under physiological conditions, both N2C- and N2D-containing NMDA receptors are crucial for excitation-inhibition balance of neuronal activity 22 . Dysfunctions of these receptors are involved in neurological and psychiatric diseases 23–28 .…”

Astrocyte GluN2C NMDA receptors control basal synaptic strengths of hippocampal CA1 pyramidal neurons in the stratum radiatum

“…This suggests that for dendritic computations in CA1 pyramidal neurons, the broad variability of synaptic strengths at CA3-CA1 synapses is more crucial compared to the synaptic strength variability of basal or apical tuft inputs. Mice deficient in GluN2C, while mostly normal in their behavior, show deficits in acquisition of conditioned fear and working memory and changes in neuronal oscillations ( Hillman et al, 2011 ; Mao et al, 2020 ). Some population of interneurons express GluN2C, however ( Gupta et al, 2016 ; Ravikrishnan et al, 2018 ), and this confounds the interpretation of the observed effects solely to deficits in astrocyte GluN2C.…”

Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model

“…We have identified that GluN2C subunits may modulate cortical oscillations ( Gupta et al, 2016 ). Specifically GluN2C knockout mice exhibit an increase in cortical oscillation in the β frequency and NMDA receptor channel blocker induced gamma oscillations are exaggerated in GluN2C knockout mice ( Gupta et al, 2016 ; Mao et al, 2020 ). Although the precise mechanism underlying modulation of oscillations in GluN2C knockout are not known, it is possible that GPe may contribute to these changes.…”