title: Juvenile treatment with a novel mGluR2 agonist/mGluR3 antagonist compound, LY395756, reverses learning deficits and cognitive flexibility impairments in adults in a neurodevelopmental model of schizophrenia.
abstract: Schizophrenia (SCZ) is a neurodevelopmental psychiatric disorder, in which cognitive function becomes disrupted at early stages of the disease. Although the mechanisms underlying cognitive impairments remain unclear, N-methyl-D-aspartate receptors (NMDAR) hypofunctioning in the prefrontal cortex (PFC) has been implicated. Moreover, cognitive symptoms in SCZ are usually unresponsive to treatment with current antipsychotics and by onset, disruption of the dopamine system, not NMDAR hypofunctioning, dominates the symptoms. Therefore, treating cognitive deficits at an early stage is a realistic approach. In this study, we tested whether an early treatment targeting mGluR2 would be effective in ameliorating cognitive impairments in the methylazoxymethanol acetate (MAM) model of SCZ. We investigated the effects of an mGluR2 agonist/mGluR3 antagonist, LY395756 (LY39), on the NMDAR expression and function in juveniles, as well as cognitive deficits in adult rats after juvenile treatment. We found that gestational MAM exposure induced a significant decrease in total protein levels of the NMDAR subunit, NR2B, and a significant increase of pNR2BTyr1472 in the juvenile rat PFC. Treatment with LY39 in juvenile MAM-exposed rats effectively recovered the disrupted NMDAR expression. Furthermore, a subchronic LY39 treatment in juvenile MAM-exposed rats also alleviated the learning deficits and cognitive flexibility impairments when tested with a cross-maze based set-shifting task in adults. Therefore, our study demonstrates that targeting dysfunctional NMDARs with an mGluR2 agonist during the early stage of SCZ could be an effective strategy in preventing the development and progression in addition to ameliorating cognitive impairments of SCZ.
authors.affiliation: Department of Rehabilitation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China; Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA; Department of Rehabilitation, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, China.
authors.forename: Meng-Lin
authors.initials: ML
authors.lastname: Li
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Gulchina
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Monaco
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xing
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Brielle R
authors.initials: BR
authors.lastname: Ferguson
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Neurobiology and Anatomy, Zhongshan School of Medicine, Sun Yat-Sen University, 510275 Guangzhou, China. Electronic address: lifeng@mail.sysu.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Rehabilitation, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, China. Electronic address: xiquhu@hotmail.com.
authors.forename: Xi-Quan
authors.initials: XQ
authors.lastname: Hu
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. Electronic address: wgao@drexelmed.edu.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Gao
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism; D004195:Disease Models, Animal; D007858:Learning / Q000187:drug effects*; D008746:Methylazoxymethanol Acetate; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*
chemical_list: C581970:2-amino-4-methylbicyclo(3.1.0)hexane2,6-dicarboxylic acid; D000600:Amino Acids, Dicarboxylic; D001643:Bridged Bicyclo Compounds; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D008746:Methylazoxymethanol Acetate
keywords: Animal model; Cognitive function; MGluR2/3; NMDA receptor; Prefrontal cortex; Schizophrenia