Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction

NMDAR antagonism alters mesolimbic, hippocampal, and cortical function, acutely reproducing the positive, cognitive, and negative symptoms of schizophrenia. These physiological and behavioral effects may depend differentially on NMDAR subtype- and region-specific effects. The dramatic electrophysiological signatures of NMDAR blockade in rodents include potentiated high frequency oscillations (HFOs, ∼140 Hz), likely generated in mesolimbic structures, and increased HFO phase-amplitude coupling (PAC), a phenomenon related to goal-directed behavior and dopaminergic tone. This study examined the impact of subtype-specific NMDAR antagonism on HFOs and PAC. We found that positive-symptom-associated NR2A-preferring antagonism (NVP-AAM077), but not NR2B-specific antagonism (Ro25-6985) or saline control, replicated increases in HFO power seen with nonspecific antagonism (MK-801). However, PAC following NR2A-preferring antagonism was distinct from all other conditions. While θ-HFO PAC was prominent or potentiated in other conditions, NVP-AAM077 increased δ-HFO PAC and decreased θ-HFO PAC. Furthermore, active wake epochs exhibiting narrowband frontal δ oscillations, and not broadband sleep-associated δ, selectively exhibited δ-HFO coupling, while paradoxical sleep epochs having a high CA1 θ to frontal δ ratio selectively exhibited θ-HFO coupling. Our results suggest: (1) NR2A-preferring antagonism induces oscillopathies reflecting frontal hyperfunction and hippocampal hypofunction; and (2) HFO PAC indexes cortical vs. hippocampal control of mesolimbic circuits.