title: mGluR2/3 agonist LY379268 rescues NMDA and GABAA receptor level deficits induced in a two-hit mouse model of schizophrenia.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
authors: Schizophrenia Research Institute, Sydney, Australia. mengel@uow.edu.au.|Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au.|Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au.|School of Biological Sciences, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au.
authors: Martin
authors: M
authors: Engel
authors: Schizophrenia Research Institute, Sydney, Australia.|Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia.|Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.
authors: Peta
authors: P
authors: Snikeris
authors: Schizophrenia Research Institute, Sydney, Australia.|Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia.|Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.
authors: Natalie
authors: N
authors: Matosin
authors: Schizophrenia Research Institute, Sydney, Australia.|Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia.|Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.
authors: Kelly Anne
authors: KA
authors: Newell
authors: Schizophrenia Research Institute, Sydney, Australia.|Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia.|Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.
authors: Xu-Feng
authors: XF
authors: Huang
authors: Schizophrenia Research Institute, Sydney, Australia.|Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.
authors: Elisabeth
authors: E
authors: Frank
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency* / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D011963:Receptors, GABA-A; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D001569:Benzodiazepines; D010622:Phencyclidine; D000077152:Olanzapine
keywords: Antipsychotic; Phencyclidine; Two hit; mGluR2/3, LY379268, agonist, NMDA receptor, GABAA receptor, schizophrenia, neuregulin 1