Journal article
LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment
Experimental neurology, v 273, pp 190-201
Nov 2015
PMID: 26341392
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Targeting group II metabotropic glutamate receptors (mGluR2/3) has been proposed to correct the dysfunctional glutamatergic system, particularly NMDA receptor (NMDAR) hypofunction, for treatment of schizophrenia. However, how activation of mGluR2/3 affects NMDAR function in adult animals remains elusive. Here we show the effects of LY395756 (LY39), a compound acting as both an mGluR2 agonist and mGluR3 antagonist, on the NMDAR expression and function of normal adult rat prefrontal cortex (PFC) as well as working memory function in the MK801 model of schizophrenia. We found that in vivo administration of LY39 significantly increased the total protein levels of NMDAR subunits and NR2B phosphorylationin the PFC, along with the amplitude of NMDAR-mediated miniature excitatory postsynaptic currents (mEPSC) in the prefrontal cortical neurons. Moreover, LY39 also significantly increased mTOR and pmTOR expression, but not ERK1/2, Akt, and GSK3β, suggesting an activation of mTOR signaling. Indeed, the mTOR inhibitor rapamycin, and actinomycin-D, a transcription inhibitor, blocked the enhanced effects of LY39 on NMDAR-mEPSCs. These results indicate that LY39 regulates NMDAR expression and function through unidentified mTOR-mediated protein synthesis in the normal adult rat PFC. However, this change is insufficient to affect working memory function in normal animals, nor to reverse the MK801-induced working memory deficit. Our data provide the first evidence of an in vivo effect of a novel compound that acts as both an mGluR2 agonist and mGluR3 antagonist on synaptic NMDAR expression and function in the adult rat PFC, although its effect -on PFC-dependent cognitive function remains to be explored.
•mGluR2 agonist LY395756 (LY39) significantly increases NMDAR expression in vivo.•LY39 also significantly increasesthe amplitude of NMDAR-mEPSCs in the PFC.•LY39 significantly increases mTOR expression, but not ERK, Akt, and GSK3β.•mTOR inhibitor rapamycin blocks the enhancing effects of LY39 on NMDAR-mEPSCs.•LY39 fails to improve working memory and reverse MK801-induced memory deficit.
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Details
- Title
- LY395756, an mGluR2 agonist and mGluR3 antagonist, enhances NMDA receptor expression and function in the normal adult rat prefrontal cortex, but fails to improve working memory and reverse MK801-induced working memory impairment
- Creators
- Meng-Lin Li - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USASha-Sha Yang - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USABo Xing - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USABrielle R Ferguson - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USAYelena Gulchina - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USAYan-Chun Li - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USAFeng Li - Department of Neurobiology and Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510275, ChinaXi-Quan Hu - Department of Rehabilitation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, ChinaWen-Jun Gao - Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA
- Publication Details
- Experimental neurology, v 273, pp 190-201
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000365151800018
- Scopus ID
- 2-s2.0-84941269137
- Other Identifier
- 991014878331604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Neurosciences