The Role Of Kv10.2 In The Emotional And Cognitive Dysfunction Of Temporal Lobe Epilepsy Rats

Epilepsy is a common neurological disease,which is characterized by the sudden abnormal discharge of neurons in the brain,leading to a chronic disease of brain dysfunction,and resulting in neurobiological,cognitive and psychological disorders.Temporary lobe epilepsy(TLE)is the most common drug-resistant and refractory epilepsy,and its etiology and clinical manifestations are quite different from×××.Voltage-gated potassium(Kv)channels are widely expressed in the central and peripheral nervous system and are crucial mediators of neuronal excitability.Importantly,these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death processes of neurons.It has been reported that functional mutations of Kv10.2 can induce epilepsy.However,the physiological function of Kv10.2 in the central nervous system is still unclear.This study is to further explore the molecular mechanism of Kv10.2 in regulating hippocampal nerve signal transmission in TLE rats in order to provide new ideas for the treatment of epilepsy.(1)In the damaged hippocampus of temporal lobe epilepsy(TLE)rats induced by kainic acid(KA),the protein expression of Kv10.2 was low.TLE rats showed obvious anxiety in the open field and elevated plus maze.TLE rats showed impaired learning and memory in Y maze and Morris water maze.The protein expression of AMPA,NMDA and GABA receptor were found to be abnormal in the damaged hippocampus.(2)The EEG results showed that TLE rats had no convulsive behavior during the inter-seizure period.There was no explosive spike or cluster spike in the local field potential(LFP).During PTZ-induced acute convulsion,neurons in the CA3 of hippocampus showed explosive and clustered spikes.The power ofδ,θ,α,βandγrhythm in TLE rats were increased during the acute convulsion.(3)Up-regulating the expression of Kv10.2 protein in the hippocampus of TLE rats showed reduced anxiety in the opening and elevated plus maze and improved learning and memory in Y maze and Morris water maze.At the same time,the number of SRS and seizure stage in TLE rats were reduced.Up-regulating the protein expression of Kv10.2 in hippocampus of TLE rats rescued the abnormal expression of AMPA,NMDA and GABA receptor.(4)Up-regulating the expression of Kv10.2 protein in hippocampal of TLE rats can decrease the power of LFP during the interictal period of epileptic seizures.In addition,up-regulating the expression of Kv10.2 protein can also reduce the high frequency and amplitude of spike activities in TLE rats induced by PTZ.(5)Kv10.2 knockout rats showed normal behavior.In the open field,elevated plus maze and black and white box tests,Kv10.2 knockout rats had no anxiety.The Y maze and Morris water maze experiments showed normal learning and memory ability.(6)The development of neuronal cells in the hippocampus of Kv10.2 knockout rats was abnormal.In addition,the expression and the area of positive spots co-labeled with MAP2 of Synapsin I and PSD95 were increased.The expression of excitatory and inhibitory receptor was unbalanced in the hippocampus of Kv10.2 knockout rats.(7)Whole cell patch-clamp recordings of brain slices in the CA3 subarea of hippocampus revealed that Kv10.2 KO increased the amplitude of excitatory postsynaptic currents(EPSC)with an undifferentiated frequency,depolarized the resting membrane potential and increased the action potential firing,reduced the rheobase and increased the input resistance。(8)Kv10.2 knockout rats showed that the power of theδ,θ,αandβrhythms was increased in the CA3 of hippocampus.Kv10.2 knockout rats reduced the incubation period of acute seizures induced by PTZ and prolonged the seizure time.In addition,Kv10.2 knockout rats increased the high frequency and amplitude of spike activities of the hippocampus.In summary,the results suggest that voltage-gated K~+channel Kv10.2 is an effective regulator of the excitability of hippocampus neurons.The expression level of Kv10.2 in the hippocampus of TLE rats was closely related to anxiety,learning and cognition,and the mechanism of excitatory and inhibitory receptors balance.Kv10.2knockout rats showed normal behavioral characteristics,but enhanced neuronal excitability in the hippocampal,and the excitatory inhibitory receptor imbalance.To study the mechanism of Kv10.2 in the occurrence and development of epilepsy,Kv10.2has the potential to become a target for epilepsy treatment.