Subunit-specific NMDAR antagonism dissociates schizophrenia subtype-relevant oscillopathies associated with frontal hypofunction and hippocampal hyperfunction.
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ABSTRACT: 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 ?-HFO PAC was prominent or potentiated in other conditions, NVP-AAM077 increased ?-HFO PAC and decreased ?-HFO PAC. Furthermore, active wake epochs exhibiting narrowband frontal ? oscillations, and not broadband sleep-associated ?, selectively exhibited ?-HFO coupling, while paradoxical sleep epochs having a high CA1 ? to frontal ? ratio selectively exhibited ?-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.
SUBMITTER: Pittman-Polletta B
PROVIDER: S-EPMC6072790 | biostudies-literature |
REPOSITORIES: biostudies-literature
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