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bioRxiv · 10.1101/191882

Modeling the schizophrenias: subunit-specific NMDAR antagonism dissociates oscillatory signatures of frontal hypofunction and hippocampal hyperfunction

Pittman-Polletta, B. R.·Hu, K.·Kocsis, B.
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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{theta} -HFO PAC was prominent or potentiated in other conditions, NVP-AAM077 increased{delta} -HFO PAC and decreased{theta} -HFO PAC. Furthermore, active wake epochs exhibiting narrowband frontal{delta} oscillations, and not broadband sleep-associated{delta} , selectively exhibited{delta} -HFO coupling, while paradoxical sleep epochs having a high CA1{theta} to frontal{delta} ratio selectively exhibited{theta} -HFO coupling. Our results suggest: (1) NR2A-preferring antagonism induces oscillopathies re[fl]ecting frontal hyperfunction and hippocampal hypofunction; and (2) HFO PAC indexes cortical vs. hippocampal control of mesolimbic circuits.

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Pittman-Polletta, B. R., Hu, K., Kocsis, B.. 2017-09-21. Modeling the schizophrenias: subunit-specific NMDAR antagonism dissociates oscillatory signatures of frontal hypofunction and hippocampal hyperfunction. https://doi.org/10.1101/191882

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