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Postnatal Administration of Dizocilpine Inhibits Neuronal Excitability in PFC and Induces Social Deficits Detected by MiceProfiler

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Abstract

Schizophrenia is a devastating mental disease with social deficit as its core component of negative symptoms, which could be induced in rodents by dizocilpine (MK-801), a noncompetitive NMDA receptor antagonist. NMDA receptors are highly expressed during the postnatal period. However, less attention has been paid to the effects of postnatal MK-801 administration on social interaction. In this study, we evaluated the effects of postnatal administration of MK-801 on social interaction and explored the possible mechanisms. Postnatal day-7 mice were intraperitoneally injected with MK-801 twice daily for 5 days, and their social interaction repertoire was monitored by a computerized video in the 10th week. The contact event, relative position event, stop-state, and dynamic event were analyzed with MiceProfiler automatic idTracker system. The results showed that MK-801 reduced the number of the contact events, relative position events, and stop-states, while increased the number and duration of dynamic events. These changes implied that MK-801-injected mice had indifference and lower motivation in social interaction and could be a useful model for studies on the social deficit of schizophrenia. The prefrontal cortex is the key region for social interaction behaviors. Slice patch clamp was performed to analyze the cellular excitability of prefrontal cortical neurons after postnatal treatment with MK-801 in mice. The results demonstrated that MK-801 injection reduced the frequency and amplitude of action potentials, but increased the frequency of miniature inhibitory postsynaptic currents. These data illustrated that the excitability of neurons in the prefrontal cortex was inhibited. Finally, immunoblotting data demonstrated that MK-801 significantly decreased the levels of sirtuin 1 (SIRT1) and phosphorylated protein kinase B (p-PKB) in the prefrontal cortex (both P < 0.05). Taken together, our results indicated that administration of MK-801 to postnatal mice induces social interaction deficits possibly due to inhibiting the neuronal excitability and decreasing the levels of SIRT1 and p-PKB in the prefrontal cortex.

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Abbreviations

MK-801:

Dizocilpine

SIRT1:

Sirtuin 1

mIPSC:

Miniature inhibitory postsynaptic currents

TTX:

Tetrodotoxin

p-PKB:

Phosphorylated protein kinase B

p-mTOR:

Phosphorylated mechanistic target of rapamycin (serine/threonine kinase)

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Acknowledgements

This study was supported by grants of National Natural Science Foundation of China (No. 81371471 and No. 81671320) and a grant of the Key Research and Development Program of Shandong Province (No.2016GSF201054). Especially, we thank the MiceProfiler software from Institut Pasteur.

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Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Shandong University, Jinan, Shandong, 250012, China

    Dexiao Zhu, Hui Wang, Jintao Wu, Qian Wang, Yue Zhao, Kunkun Pang, Qingqing Shi, Wenbo Zhao, Jing Zhang & Jinhao Sun

  2. Department of Rehabilitation, Qilu Children’s Hospital, Shandong University, Jinan, Shandong, China

    Ling Xu

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  1. Dexiao Zhu
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Correspondence to Jinhao Sun.

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All mice were used in accordance with the National Institutes of Health Guide for the care and use of laboratory animals.

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The authors declare that they have no conflict of interest.

Additional information

Dexiao Zhu and Hui Wang contributed equally to this work.

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Zhu, D., Wang, H., Wu, J. et al. Postnatal Administration of Dizocilpine Inhibits Neuronal Excitability in PFC and Induces Social Deficits Detected by MiceProfiler. Mol Neurobiol 54, 8152–8161 (2017). https://doi.org/10.1007/s12035-016-0291-7

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