Martin Engel1,2,3,4, Peta Snikeris5,6,7, Natalie Matosin5,6,7, Kelly Anne Newell5,6,7, Xu-Feng Huang5,6,7, Elisabeth Frank5,7. 1. Schizophrenia Research Institute, Sydney, Australia. mengel@uow.edu.au. 2. Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au. 3. Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au. 4. School of Biological Sciences, University of Wollongong, Wollongong, Australia. mengel@uow.edu.au. 5. Schizophrenia Research Institute, Sydney, Australia. 6. Faculty of Science Medicine and Health, University of Wollongong, Wollongong, Australia. 7. Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, Australia.
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.
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 (NRG1HET) 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 NRG1HETmice, 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 schizophreniamouse 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: Russell C Callaghan; James K Cunningham; Peter Allebeck; Tamara Arenovich; Gautam Sajeev; Gary Remington; Isabelle Boileau; Stephen J Kish Journal: Am J Psychiatry Date: 2012-04 Impact factor: 18.112
Authors: W Michael Bullock; Federico Bolognani; Paolo Botta; C Fernando Valenzuela; Nora I Perrone-Bizzozero Journal: Neurochem Int Date: 2009-08-03 Impact factor: 3.921