SCIENCE@home

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

B. Pittman-Polletta,Kun Hu,B. Kocsis

Published 2017 in bioRxiv

ABSTRACT

NMDAR antagonism alters mesolimbic, hippocampal, and cortical function, and acutely reproduces the positive, cognitive, and negative symptoms of schizophrenia. Evidence suggests these physiological and behavioral consequences may depend differentially on NMDAR subtype-and region-specific effects. One of the most dramatic electrophysiological signatures of NMDAR blockade in rodents is the potentiation of narrowband high frequency oscillations (HFOs, ∼140 Hz) and their phase coupling to θ and δ oscillations. The mechanisms generating HFOs are unknown, but evidence implicates mesolimbic structures, and HFO phase-amplitude coupling (PAC) is related to goal-directed behavior and dopaminergic tone. The goal of this study was to examine 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 abnormal 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 associated with elevated hippocampal θ rhythm, NVP-AAM077 increased δ-HFO PAC and decreased θ-HFO PAC 2-4 hours after administration. δ-HFO PAC was correlated with frontal δ power and θ-HFO PAC was correlated with hippocampal θ power. Furthermore, wake epochs exhibiting narrowband frontal δ oscillations, and not broadband δ characteristic of sleep, selectively exhibited δ-HFO coupling, while paradoxical sleep epochs having a high hippocampal θ /δ ratio selectively exhibited θ-HFO coupling. These results suggest: (1) NR2A-preferring antagonism induces oscillopathies reflecting frontal and subcortical hyperfunction and hippocampal hypofunction; and (2) low-frequency modulation of HFO amplitude may index cortical vs. hippocampal control of mesolimbic circuits.

PUBLICATION RECORD

  • Publication year

    2017

  • Venue

    bioRxiv

  • Publication date

    2017-09-25

  • Fields of study

    Biology, Medicine, Chemistry, Psychology

  • Identifiers
    DOI 10.1101/191882
  • External record

    Open on Semantic Scholar

  • Source metadata

    Semantic Scholar

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-70 of 70 references · Page 1 of 1

CITED BY