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

Psychopharmacology (Berl). 2016 Apr;233(8):1349-59. doi: 10.1007/s00213-016-4230-0. Epub 2016 Feb 10.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / pharmacology*
  • Animals
  • Antipsychotic Agents / pharmacology
  • Benzodiazepines / pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Olanzapine
  • Phencyclidine / pharmacology
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Receptors, GABA-A / deficiency*
  • Receptors, GABA-A / metabolism
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism
  • Receptors, N-Methyl-D-Aspartate / deficiency*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Schizophrenia / metabolism*


  • Amino Acids
  • Antipsychotic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • LY 379268
  • Receptors, GABA-A
  • Receptors, Metabotropic Glutamate
  • Receptors, N-Methyl-D-Aspartate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3
  • Benzodiazepines
  • Phencyclidine
  • Olanzapine