Yurie Matsumoto1,2, Minae Niwa3,4,5, Akihiro Mouri1,6,7, Yukihiro Noda7,8, Takeshi Fukushima9, Norio Ozaki2, Toshitaka Nabeshima10,11,12,13. 1. Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, 468-8503, Japan. 2. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan. 3. Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, 468-8503, Japan. mniwa1@jhmi.edu. 4. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan. mniwa1@jhmi.edu. 5. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. mniwa1@jhmi.edu. 6. Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Science, Toyoake, 470-1192, Japan. 7. NPO Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan. 8. Division of Clinical Sciences and Neuropsychopharmacology, Graduate School of Pharmacy, Meijo University, Nagoya, 468-8503, Japan. 9. Department of Analytical Chemistry, Faculty of Pharmaceutical Science, Toho University, Chiba, 274-8510, Japan. 10. Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, 468-8503, Japan. tnabeshi@ccalumni.meijo-u.ac.jp. 11. Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Science, Toyoake, 470-1192, Japan. tnabeshi@ccalumni.meijo-u.ac.jp. 12. NPO Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan. tnabeshi@ccalumni.meijo-u.ac.jp. 13. Aino University, Ibaragi, Osaka, 567-0012, Japan. tnabeshi@ccalumni.meijo-u.ac.jp.
Abstract
BACKGROUND: Stress during the adolescent period influences postnatal maturation and behavioral patterns in adulthood. Adolescent stress-induced molecular and functional changes in neurons are the key clinical features of psychiatric disorders including schizophrenia. OBJECTIVE: In the present study, we exposed genetically vulnerable mice to isolation stress to examine the molecular changes in the glutamatergic system involving N-methyl-d-aspartate (NMDA) receptors via dopaminergic disturbance in the prefrontal cortex (PFc). RESULTS: We report that late adolescent stress in combination with Disrupted-in-Schizophrenia 1 (DISC1) genetic risk elicited alterations in glutamatergic neurons in the PFc, such as increased expression of glutamate transporters, decreased extracellular levels of glutamate, decreased concentration of d-serine, and impaired activation of NMDA-Ca2+/calmodulin kinase II signaling. These changes resulted in behavioral deficits in locomotor activity, forced swim, social interaction, and novelty preference tests. The glutamatergic alterations in the PFc were prevented if the animals were treated with an atypical antipsychotic drug clozapine and a dopamine D1 agonist SKF81297, which suggests that the activation of dopaminergic neurons is involved in the regulation of the glutamatergic system. CONCLUSION: Our results suggest that adolescent stress combined with dopaminergic abnormalities in the PFc of genetically vulnerable mice induces glutamatergic disturbances, which leads to behavioral deficits in the young adult stage.
BACKGROUND:Stress during the adolescent period influences postnatal maturation and behavioral patterns in adulthood. Adolescent stress-induced molecular and functional changes in neurons are the key clinical features of psychiatric disorders including schizophrenia. OBJECTIVE: In the present study, we exposed genetically vulnerable mice to isolation stress to examine the molecular changes in the glutamatergic system involving N-methyl-d-aspartate (NMDA) receptors via dopaminergic disturbance in the prefrontal cortex (PFc). RESULTS: We report that late adolescent stress in combination with Disrupted-in-Schizophrenia 1 (DISC1) genetic risk elicited alterations in glutamatergic neurons in the PFc, such as increased expression of glutamate transporters, decreased extracellular levels of glutamate, decreased concentration of d-serine, and impaired activation of NMDA-Ca2+/calmodulin kinase II signaling. These changes resulted in behavioral deficits in locomotor activity, forced swim, social interaction, and novelty preference tests. The glutamatergic alterations in the PFc were prevented if the animals were treated with an atypical antipsychotic drug clozapine and a dopamine D1 agonist SKF81297, which suggests that the activation of dopaminergic neurons is involved in the regulation of the glutamatergic system. CONCLUSION: Our results suggest that adolescent stress combined with dopaminergic abnormalities in the PFc of genetically vulnerable mice induces glutamatergic disturbances, which leads to behavioral deficits in the young adult stage.
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