The potential of the P2X7 receptor as a therapeutic target in a sub-chronic PCP-induced rodent model of schizophrenia

Hui Huang; Suyue Zheng; Min Chen; Liyuan Xie; Ziyi Li; Min Guo; Jianhong Wang; Mingwei Lu; Xingen Zhu

doi:10.1016/j.jchemneu.2021.101993

The potential of the P2X7 receptor as a therapeutic target in a sub-chronic PCP-induced rodent model of schizophrenia

J Chem Neuroanat. 2021 Oct:116:101993. doi: 10.1016/j.jchemneu.2021.101993. Epub 2021 Jun 17.

Authors

Hui Huang¹, Suyue Zheng², Min Chen¹, Liyuan Xie¹, Ziyi Li¹, Min Guo³, Jianhong Wang⁴, Mingwei Lu⁵, Xingen Zhu⁶

Affiliations

¹ Department of Neurosurgery, Second Affiliation Hospital, Nanchang University, Nanchang, Jiangxi, China; Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, China.
² Department of Neurosurgery, First Affiliation Hospital, Nanchang University, Nanchang, Jiangxi, China.
³ Psychosomatic Medicine, Second Affiliation Hospital, Nanchang University, Nanchang, Jiangxi, China.
⁴ Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences, Kunming Institute of Zoology, Kunming, Yunnan, China.
⁵ Department of Neurosurgery, Second Affiliation Hospital, Nanchang University, Nanchang, Jiangxi, China; Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, China. Electronic address: [email protected].
⁶ Department of Neurosurgery, Second Affiliation Hospital, Nanchang University, Nanchang, Jiangxi, China; Institute of Neuroscience, Nanchang University, Nanchang, Jiangxi, China. Electronic address: [email protected].

PMID: 34147620
DOI: 10.1016/j.jchemneu.2021.101993

Abstract

Objective: We studied the role of the P2X7 receptor on cognitive dysfunction in a mouse model of schizophrenia.

Methods: An adult mouse model was established by treatment with phencyclidine (PCP), an N-methyl-D-aspartate (NMDA) receptor antagonist. Young mice were divided into three groups: 1) the control (saline-injected) group; 2) experimental 5 mg/kg PCP-injected group; and 3) experimental 10 mg/kg PCP-injected group. The mice were subjected to the open-field and Morris water maze tests at 7 weeks. After intraperitoneal injection of the P2X7 receptor antagonist JNJ-47965567, the behaviour tests were performed again. Samples were taken after testing. The P2X7 receptor protein and mRNA expression levels were detected by immunohistochemistry, Western blotting and PCR.

Results: This study revealed that the infant sub-chronic PCP mice model showed severe spatial learning and memory impairment in the Morris water maze and schizophrenia-like symptoms (hypermotor behaviour) in the open-field test. The P2X7 receptor protein was highly expressed in the sub-chronic PCP mouse model and more highly expressed in the hippocampus than the prefrontal lobe. After the P2X7 receptor was blocked with JNJ-47965567, P2X7 receptor protein and mRNA expression in the frontal lobe were significantly increased, and the spatial memory impairment and hypermotor behaviour induced by PCP were reversed.

Conclusion: PCP-induced cognitive impairment can be significantly improved by antagonizing the P2X7 receptor. Therefore, we believe that the P2X7 receptor plays an important role in the cognition of schizophrenic-like mice.

Keywords: Cognitive disorder; P2X7 receptor; PCP; Schizophrenia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Drug Delivery Systems / methods*
Hallucinogens / toxicity
Injections, Subcutaneous
Male
Mice
Mice, Inbred C57BL
Niacinamide / administration & dosage
Niacinamide / analogs & derivatives
Phencyclidine / toxicity*
Piperazines / administration & dosage
Purinergic P2X Receptor Antagonists / administration & dosage*
Receptors, Purinergic P2X7 / metabolism*
Rodentia
Schizophrenia / chemically induced
Schizophrenia / drug therapy*
Schizophrenia / metabolism*

Substances

Hallucinogens
JNJ-47965567
Piperazines
Purinergic P2X Receptor Antagonists
Receptors, Purinergic P2X7
Niacinamide
Phencyclidine