title: Subchronic pharmacological and chronic genetic NMDA receptor hypofunction differentially regulate the Akt signaling pathway and Arc expression in juvenile and adult mice.
abstract: NMDA receptor (NMDAR) hypofunction is a compelling hypothesis for the pathophysiology of schizophrenia, because in part, NMDAR antagonists cause symptoms in healthy adult subjects that resemble schizophrenia. Therefore, NMDAR antagonists have been used as a method to induce NMDAR hypofunction in animals as a pharmacological model of schizophrenia. Serine racemase-null mutant (SR-/-) mice display constitutive NMDAR hypofunction due to the lack of d-serine. SR-/- mice have deficits in tropomyosin-related kinase receptor (TrkB)/Akt signaling and activity regulated cytoskeletal protein (Arc) expression, which mirror what is observed in schizophrenia. Thus, we analyzed these signaling pathways in MK801 sub-chronically (0.15mg/kg; 5days) treated adult wild-type mice. We found that in contrast to SR-/- mice, the activated states of downstream signaling molecules, but not TrkB, increased in MK801 treated mice. Furthermore, there is an age-dependent change in the behavioral reaction of people to NMDAR antagonists. We therefore administered the same dosing regimen of MK801 to juvenile mice and compared them to juvenile SR-/- mice. Our findings demonstrate that pharmacological NMDAR antagonism has different effects on TrkB/Akt signaling than genetically-induced NMDAR hypofunction. Given the phenotypic disparity between the MK801 model and schizophrenia, our results suggest that SR-/- mice more accurately reflect NMDAR hypofunction in schizophrenia.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. Electronic address: stakagi@mclean.harvard.edu.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Takagi
authors.affiliation: Department of Psychiatry, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
authors.forename: Darrick T
authors.initials: DT
authors.lastname: Balu
authors.affiliation: Department of Psychiatry, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Laboratory for Psychiatric and Molecular Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. Electronic address: joseph_coyle@hms.harvard.edu.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Coyle
mesh_terms: D000375:Aging; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019998:Racemases and Epimerases / Q000172:deficiency / Q000235:genetics; D020813:Receptor, trkB / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D012559:Schizophrenia / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000099300:Serine Racemase
chemical_list: D003598:Cytoskeletal Proteins; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D038362:Glycogen Synthase Kinase 3; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; D019998:Racemases and Epimerases; D020813:Receptor, trkB; D016194:Receptors, N-Methyl-D-Aspartate; D000099300:Serine Racemase; C092069:activity regulated cytoskeletal-associated protein
keywords: MK801; Schizophrenia; Serine racemase; Tropomyosin receptor kinase B (TrkB); d-Serine