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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

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Abstract

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.

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Abbreviations

SZ:

Schizophrenia

CNS:

The central nervous system

GAD67:

Glutamate decarboxylase 1 (GAD67)

PV:

Parvalbumin

NRG1:

Neuregulin 1

NMDA:

N-methyl-d-aspartate

PPI:

Prepulse inhibition

NORT:

Novel object recognition test

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81171268).

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Authors and Affiliations

  1. Department of Laboratory of the Second Xiangya Hospital, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, Hunan, China

    Cunyan Li, Yamei Tang, Jingjing Yang & Aiguo Tang

  2. 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 Zhang & Yong Liu

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  1. Cunyan Li
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Correspondence to Yong Liu or Aiguo Tang.

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Li, C., Tang, Y., Yang, J. et al. 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. Neurochem Res 41, 2049–2064 (2016). https://doi.org/10.1007/s11064-016-1917-x

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