Psychopharmacology

, Volume 233, Issue 8, pp 1349–1359 | Cite as

mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia

  • Martin Engel
  • Peta Snikeris
  • Natalie Matosin
  • Kelly Anne Newell
  • Xu-Feng Huang
  • Elisabeth Frank
Original Investigation

Abstract

Rationale

An imbalance of excitatory and inhibitory neurotransmission underlies the glutamate hypothesis of schizophrenia. Agonists of group II metabotropic glutamate receptors, mGluR2/3, have been proposed as novel therapeutic agents to correct this imbalance. However, the influence of mGluR2/3 activity on excitatory and inhibitory neurotransmitter receptors has not been explored.

Objectives

We aimed to investigate the ability of a novel mGluR2/3 agonist, LY379268, to modulate the availability of the excitatory N-methyl-d-aspartate receptor (NMDA-R) and the inhibitory gamma-aminobutyrate-A receptor (GABAA-R), in a two-hit mouse model of schizophrenia.

Methods

Wild type (WT) and heterozygous neuregulin 1 transmembrane domain mutant mice (NRG1 HET) were treated daily with phencyclidine (10 mg/kg ip) or saline for 14 days. After a 14-day washout, an acute dose of the mGluR2/3 agonist LY379268 (3 mg/kg), olanzapine (antipsychotic drug comparison, 1.5 mg/kg), or saline was administered. NMDA-R and GABAA-R binding densities were examined by receptor autoradiography in several schizophrenia-relevant brain regions.

Results

In both WT and NRG1 HET mice, phencyclidine treatment significantly reduced NMDA-R and GABAA-R binding density in the prefrontal cortex, hippocampus, and nucleus accumbens. Acute treatment with LY379268 restored NMDA-R and GABAA-R levels in the two-hit mouse model comparable to olanzapine.

Conclusions

We demonstrate that the mGluR2/3 agonist LY379268 restores excitatory and inhibitory deficits with similar efficiency as olanzapine in our two-hit schizophrenia mouse model. This study significantly contributes to our understanding of the mechanisms underlying the therapeutic effects of LY379268 and supports the use of agents aimed at mGluR2/3.

Keywords

mGluR2/3, LY379268, agonist, NMDA receptor, GABAA receptor, schizophrenia, neuregulin 1 Phencyclidine Two hit Antipsychotic 

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Martin Engel
    • 1
    • 2
    • 3
    • 4
  • Peta Snikeris
    • 1
    • 2
    • 3
  • Natalie Matosin
    • 1
    • 2
    • 3
  • Kelly Anne Newell
    • 1
    • 2
    • 3
  • Xu-Feng Huang
    • 1
    • 2
    • 3
  • Elisabeth Frank
    • 1
    • 3
  1. 1.Schizophrenia Research InstituteSydneyAustralia
  2. 2.Faculty of Science Medicine and HealthUniversity of WollongongWollongongAustralia
  3. 3.Illawarra Health and Medical Research InstituteUniversity of WollongongWollongongAustralia
  4. 4.School of Biological SciencesUniversity of WollongongWollongongAustralia

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