Sub-chronic Antipsychotic Drug Administration Reverses the Expression of Neuregulin 1 and ErbB4 in a Cultured MK801-Induced Mouse Primary Hippocampal Neuron or a Neurodevelopmental Schizophrenia Model.
It has been reported that specific environmental influences during the postpartum period might contribute to the development of schizophrenia (SZ). Administration of MK801 during early development led to persistent brain pathology. Glutamate decarboxylase 1 (GAD67) and parvalbumin (PV), and neuregulin 1 (NRG1)/ErbB4 signaling were closely associated with SZ pathology. We postulated therefore that NMDA receptor antagonists exposure during the postpartum period may be associated with expression dysregulation of some of the SZ candidate proteins. To test this, we used mouse primary hippocampal neurons and neonatal male mice treated with the NMDA receptor antagonist, MK801 at postnatal day 4 (P4) or P7, followed by the treatments of antipsychotic drugs (i.e., olanzapine, risperidone, and haloperidol). The expressions of GAD67, PV, NRG1, and ErbB4 in in vitro and in vivo SZ models were detected with Western blot analysis and immunohistochemistry, respectively. Behavioral tests (locomotion activity, social interaction, novel object recognition and prepulse inhibition) were measured. We found MK801 decreased the expression of GAD67, PV, NRG1 and ErbB4, and induced obvious behavioral alterations, while antipsychotics reversed these alterations. These results suggest that exposure to the NMDA receptor antagonist in early development may lead to long-lasting influence on the expression of specific proteins, such as GAD67, PV, NRG1, and ErbB4. Moreover, our results suggest that rescue of the activation of the NRG1/ErbB4 signaling pathway may be one of the mechanisms by which antipsychotic drugs have an antipsychotic effect.
Department of Laboratory of the Second Xiangya Hospital, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, Hunan, China.
Cunyan
C
Li
Department of Laboratory of the Second Xiangya Hospital, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, Hunan, China.
Yamei
Y
Tang
Department of Laboratory of the Second Xiangya Hospital, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, Hunan, China.
Jingjing
J
Yang
Mental Health Institute of the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, Hunan, China.
Xianghui
X
Zhang
Mental Health Institute of the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, Hunan, China. zjjlcy@csu.edu.cn.
Yong
Y
Liu
Department of Laboratory of the Second Xiangya Hospital, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, Hunan, China. aiguotang@aliyun.com.
Aiguo
A
Tang
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D005260:Female; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D066247:Receptor, ErbB-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D016291:Dizocilpine Maleate; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4
ErbB4; GAD67; NRG1; Neurodevelopment; Parvalbumin; Schizophrenia