title: Glutamate receptor 1 phosphorylation at serine 845 contributes to the therapeutic effect of olanzapine on schizophrenia-like cognitive impairments.
abstract: Schizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., haloperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.
authors.affiliation: Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: yirufang@aliyun.com.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China. Electronic address: lxu@vip.163.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006220:Haloperidol / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D008570:Memory, Short-Term / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D000077152:Olanzapine; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D012559:Schizophrenia / Q000150:complications / Q000188:drug therapy; D065853:Spatial Learning / Q000187:drug effects
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D018691:Excitatory Amino Acid Antagonists; D006220:Haloperidol; D000077152:Olanzapine; D018091:Receptors, AMPA
keywords: Antipsychotics; Glutamate receptor; Morris water maze; Synaptic plasticity