The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice

Elysia Sokolenko, Matthew R. Hudson, Jess Nithianantharajah, Nigel C. Jones

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Background: Abnormalities in neural oscillations that occur in the gamma frequency range (30–80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists. Aims: We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR2/3) agonist LY379268. Methods: C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus. Results: MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130–180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment. Conclusions: NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR2/3. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.

Original languageEnglish
Pages (from-to)1588-1599
Number of pages12
JournalJournal of Psychopharmacology
Volume33
Issue number12
DOIs
Publication statusPublished - 1 Dec 2019

Keywords

  • gamma oscillations
  • mGlu receptor agonist
  • mice
  • MK-801
  • NMDA receptor antagonist
  • phase coherence
  • Working memory

Cite this