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.
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.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Department of Rehabilitation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China.
Meng-Lin
ML
Li
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Sha-Sha
SS
Yang
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Bo
B
Xing
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Brielle R
BR
Ferguson
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Yelena
Y
Gulchina
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Yan-Chun
YC
Li
Department of Neurobiology and Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510275, China. Electronic address: li.feng@mail.sysu.edu.cn.
Feng
F
Li
Department of Rehabilitation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China. Electronic address: xiquhu@hotmail.com.
Xi-Quan
XQ
Hu
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address: wgao@drexelmed.edu.
Wen-Jun
WJ
Gao
D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D001288:Attention / Q000187:drug effects; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D008570:Memory, Short-Term / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D055366:Synaptic Potentials / Q000187:drug effects
C581970:2-amino-4-methylbicyclo(3.1.0)hexane2,6-dicarboxylic acid; D000600:Amino Acids, Dicarboxylic; D001643:Bridged Bicyclo Compounds; D018683:Excitatory Amino Acid Agents; D007166:Immunosuppressive Agents; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D020123:Sirolimus
Animal model; Cognitive function; NMDA receptor; Prefrontal cortex; Protein synthesis; Schizophrenia; mGluR2 agonist and mGluR3 antagonist; mTOR signaling