Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia

Abstract

Abstract: Objective: ATP-sensitive potassium (K-ATP) channels are crucial for dopaminergic and glutamatergic transmission，which has been demonstrated to be the important feature of pathophysiology in schizophrenia. We studied the effects of K-ATP channels on the phencyclidine (PCP)-induced changes in the forced swimming test (FST，an animal model of negative symptoms of schizophrenia)，using mice with knockout of the Kir6.2 (a pore-forming subunit of neuronal K-ATP channel). Methods:After repeated PCP (10 mg·kg^-1，i.p. daily for 14 days) administration，The FST were used to assess depression-related behaviors associated with negative symptoms. Striatal dopamine and dopamine turnover were measured by high pressure liquid chromatography with electrochemical detection. Cell proliferation in the subgranular zone (SGZ) was determined by bromodeoxyuridine immunohistochemistry. The expressions of total Akt and phosphorylation Akt were evaluated using Western blot. Results: After repeated PCP administration，the enhancement of immobility induced by the FST was attenuated in Kir6.2 knockout mice. Meanwhile，Kir6.2 knockout decreased striatal dopamine turnover，whereas wild-type mice exhibited an augmentation in response to PCP treatment. Furthermore，Kir6.2 knockout could prevent the inhibition of neural stem cell proliferation in the SGZ and suppressed the PCP-induced phosphorylation of Akt^Ser473. Conclusion: These results suggest a possible implication of Kir6.2-composing K-ATP channels dysfunction in the pathogenesis of negative symptoms associated with schizophrenia.

CLC Number:

R332

DAI Ting, CHEN Zhong-Guo, DUAN Lei, DING Jian-Hua, FAN Yi, HU Gang. Involvement of Kir6.2-composing ATP-sensitive potassium channels in phencyclidine-induced negative symptoms of schizophrenia[J]. ACTA NEUROPHARMACOLOGICA, 2011, 1(1): 31-38.

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