PMID- 31580222 OWN - NLM STAT- MEDLINE DCOM- 20200814 LR - 20200814 IS - 1461-7285 (Electronic) IS - 0269-8811 (Linking) VI - 33 IP - 12 DP - 2019 Dec TI - The mGluR(2/3) agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice. PG - 1588-1599 LID - 10.1177/0269881119875976 [doi] AB - 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 (mGluR(2/3)) 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 mGluR(2/3). 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. FAU - Sokolenko, Elysia AU - Sokolenko E AD - Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne Brain Centre, Parkville, VIC, Australia. FAU - Hudson, Matthew R AU - Hudson MR AD - Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne Brain Centre, Parkville, VIC, Australia. AD - Department of Neuroscience, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, VIC, Australia. FAU - Nithianantharajah, Jess AU - Nithianantharajah J AD - The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia. FAU - Jones, Nigel C AU - Jones NC AUID- ORCID: 0000-0002-1080-8439 AD - Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne Brain Centre, Parkville, VIC, Australia. AD - Department of Neuroscience, Central Clinical School, Monash University, The Alfred Hospital, Melbourne, VIC, Australia. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191003 PL - United States TA - J Psychopharmacol JT - Journal of psychopharmacology (Oxford, England) JID - 8907828 RN - 0 (Amino Acids) RN - 0 (Bridged Bicyclo Compounds, Heterocyclic) RN - 0 (Excitatory Amino Acid Antagonists) RN - 0 (LY 379268) RN - 0 (Receptors, Metabotropic Glutamate) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (metabotropic glutamate receptor 2) RN - 0 (metabotropic glutamate receptor 3) RN - 6LR8C1B66Q (Dizocilpine Maleate) SB - IM MH - Amino Acids/*pharmacology MH - Animals MH - Bridged Bicyclo Compounds, Heterocyclic/*pharmacology MH - Cognitive Dysfunction/chemically induced/drug therapy MH - Dizocilpine Maleate/administration & dosage/*toxicity MH - Dose-Response Relationship, Drug MH - Excitatory Amino Acid Antagonists/administration & dosage/*toxicity MH - Hippocampus/drug effects MH - Male MH - Memory Disorders/chemically induced/drug therapy MH - Memory, Short-Term/drug effects MH - Mice MH - Mice, Inbred C57BL MH - Prefrontal Cortex/drug effects MH - Receptors, Metabotropic Glutamate/agonists MH - Receptors, N-Methyl-D-Aspartate/*drug effects/metabolism OTO - NOTNLM OT - MK-801 OT - NMDA receptor antagonist OT - Working memory OT - gamma oscillations OT - mGlu2/3 receptor agonist OT - mice OT - phase coherence EDAT- 2019/10/04 06:00 MHDA- 2020/08/15 06:00 CRDT- 2019/10/04 06:00 PHST- 2019/10/04 06:00 [pubmed] PHST- 2020/08/15 06:00 [medline] PHST- 2019/10/04 06:00 [entrez] AID - 10.1177/0269881119875976 [doi] PST - ppublish SO - J Psychopharmacol. 2019 Dec;33(12):1588-1599. doi: 10.1177/0269881119875976. Epub 2019 Oct 3.