Effect And Mechanism Of Inhibiting The Forebrain Kv7 Channel To Improve MK-801-induced Schizophrenia-like Cognitive Impairments

The forebrain is profusely connected with other parts of the brain critical for cognitive and emotional behaviors.Dysfunctional forebrain is implicated in cognitive deficits in schizophrenia.The Kv7/KCNQ channels are voltage-gated potassium channels that exert functional effect on the regulation of physiological processes such as neuronal excitability,neurotransmitter release and synaptic transmission.Previous studies have shown that inhibiting M currents can increase excitability of neurons and excitatory synaptic response in the forebrain,thus improving cognitive deficits.Therefore,enhancing the forebrain excitability by regulating Kv7 channel function may be important for improving cognitive impairment in schizophrenia patients.Objective: Mouse model of schizophrenia-like cognitive impairment is established by MK-801.After administration of Kv7 channel opener or inhibitor,the role of forebrain Kv7 channel in schizophrenia-like cognitive impairment is investigated to identify whether Kv7 channel can be used as a target for the development of drugs to improve cognitive impairment,thus providing experimental basis for the development of drugs to treat cognitive impairment in schizophrenia.Methods: In this study,rKCNQ2-G279 S transgenic mice and wild type mice treated with Kv7 channel inhibitor XE991 were used to inhibit Kv7 channel by genetic or pharmacological means.Mouse model of cognitive impairment was established by single intraperitoneal(i.p.)injection of 0.1 mg/kg MK-801.Mouse models of prepulse inhibition(PPI)of acoustic startle reflex and Y-maze of spatial recognition memory tests were used for evaluation of cognitive behavior.Hippocampal brain slice recordings of long-term potentiation(LTP),input-output curves(I/O curves)and paired-pulse facilitation(PPF)were carried out for examining synaptic plasticity and synaptic transmission.Western blot analysis was used to detect the expression changes of key proteins in Akt1/GSK-3? signaling pathway closely related to schizophrenia.Results: 1.In the PPI experiment,rKCNQ2-G279 S transgenic mice showed enhanced PPI level and were resistant to MK-801(0.1 mg/kg,i.p.)induced PPI injury by genetically inhibiting Kv7 channel.Pharmacological inhibition of Kv7 channel by injection of XE991(1 mg/kg,i.p.)attenuated the MK-801 induced PPI damage.2.In the Y-maze experiment,the time spent in novel arm of rKCNQ2-G279 S transgenic mice significantly increased via genetic inhibition of Kv7 channel.Pharmacological inhibition of Kv7 channel by injection of XE991(1 mg/kg,i.p.)significantly prolonged the time that MK-801(0.1 mg/kg,i.p.)treated mice moved in novel arm.3.Electrophysiological recordings showed that MK-801(0.1 mg/kg,i.p.)significantly decreased the LTP amplitude induced by high-frequency stimulation and the slope of I/O curve.XE991(1 mg/kg,i.p.)reversed the MK-801 induced LTP deficit and increased the slope of I/O curve.The results of PPF recordings showed that MK-801(0.1 mg/kg,i.p.)significantly decreased the PPF,but administration of XE991(1 mg/kg,i.p.)had little effect on the PPF.4.The western blot analysis showed that the expression levels of pAkt1 and pGSK-3? in hippocampus and cortex of rKCNQ2-G279 S transgenic mice significantly increased,and transgenic mice were resilient to MK-801(0.1 mg/kg,i.p.)induced reduction of these proteins induced by through genetic inhibition of Kv7 channel.Pharmacological inhibition of Kv7 channel by administration of XE991(1 mg/kg,i.p.)reversed MK-801(0.1 mg/kg,i.p.)induced decreases of the protein expression levels of pAkt1,pGSK-3? and ?-catenin in the hippocampus and cortex.Conclusions: Genetic or pharmacological inhibition of neuronal Kv7 channel improves PPI of acoustic startle response and spatial working memory impairments.Mechanistically,inhibition of Kv7 channel promotes synaptic transmission and synaptic plasticity,and activates the Akt1/GSK-3? signaling.Therefore,pharmacological inhibition of neuronal Kv7 channel may possess therapeutic potential for improvement of schizophrenia-like cognitive deficits.