Objective Motor control is encoded by neuronal activity. Small conductance Ca2＋-activated K＋ channels （SK channels） maintain the regularity and precision of firing by contributing to the afterhyperpolarization （...Objective Motor control is encoded by neuronal activity. Small conductance Ca2＋-activated K＋ channels （SK channels） maintain the regularity and precision of firing by contributing to the afterhyperpolarization （AHP） of the action potential in mammals. However, it is not clear how SK channels regulate the output of the vocal motor system in songbirds. The premotor robust nucleus of the arcopallium （RA） in the zebra finch is responsible for the output of song information. The temporal pattern of spike bursts in RA projection neurons is associated with the timing of the acoustic features of birdsong. Methods The firing properties of RA projection neurons were analyzed using patch clamp whole-cell and cell-attached recording techniques. Results SK channel blockade by apamin decreased the AHP amplitude and increased the evoked firing rate in RA projection neurons. It also caused reductions in the regularity and precision of firing. RA projection neurons displayed regular spontaneous action potentials, while apamin caused irregular spontaneous firing but had no effect on the firing rate. In the absence of synaptic inputs, RA projection neurons still had spontaneous firing, and apamin had an evident effect on the firing rate, but caused no significant change in the firing regularity, compared with apamin application in the presence of synaptic inputs. Conclusion SK channels contribute to the maintenance of firing regularity in RA projection neurons which requires synaptic activity, and consequently ensures the precision of song encoding.展开更多
Neurons in the brain utilize various firing trains to encode the input signals they have received. Firing behavior of one single neuron is thoroughly explained by using a bifurcation diagram from polarized resting to ...Neurons in the brain utilize various firing trains to encode the input signals they have received. Firing behavior of one single neuron is thoroughly explained by using a bifurcation diagram from polarized resting to firing, and then to depolarized resting. This explanation provides an important theoretical principle for understanding neuronal biophysical behaviors. This paper reports the novel experimental and modeling results of the modification of such a bifurcation dia- gram by adjusting small conductance potassium （SK） channel. In experiments, changes in excitability and depolarization block in nucleus accumbens shell and medium-spiny projection neurons are explored by increasing the intensity of injected current and blocking the SK channels by apamin. A shift of bifurcation points is observed. Then, a Hodgkin-Huxley type model including the main electrophysiological processes of such neurons is developed to reproduce the experimental results. The reduction of SK channel conductance also shifts the bifurcations, which is in consistence with experiment. A global bifurcation paradigm of this shift is obtained by adjusting two parameters, intensity of injected current and SK channel con- ductance. This work reveals the dynamics underpinning modulation of neuronal firing behaviors by biologically important ionic conductance. The results indicate that small ionic conductance other than that responsible for spike generation can modify bifurcation points and shift the bifurcation diagram and, thus, change neuronal excitability and adaptation.展开更多
The pathogenesis of the second major neurodegenerative disorder, Parkinson’s disease(PD), is closely associated with the dysfunction of potassium(K~+ ) channels. Therefore, PD is also considered to be an ion channel ...The pathogenesis of the second major neurodegenerative disorder, Parkinson’s disease(PD), is closely associated with the dysfunction of potassium(K~+ ) channels. Therefore, PD is also considered to be an ion channel disease or neuronal channelopathy. Mounting evidence has shown that K~+ channels play crucial roles in the regulations of neurotransmitter release, neuronal excitability, and cell volume. Inhibition of K~+ channels enhances the spontaneous firing frequency of nigral dopamine(DA)neurons, induces a transition from tonic firing to burst discharge, and promotes the release of DA in the striatum.Recently, three K~+ channels have been identified to protect DA neurons and to improve the motor and non-motor symptoms in PD animal models: small conductance(SK)channels, A-type K~+ channels, and KV7/KCNQ channels.In this review, we summarize the physiological and pharmacological effects of the three K~+ channels. We also describe in detail the laboratory investigations regarding K~+ channels as a potential therapeutic target for PD.展开更多
The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium inf...The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.展开更多
基金supported by grants from the National Natural Science Foundation of China (30970363 and 31172092)
文摘Objective Motor control is encoded by neuronal activity. Small conductance Ca2＋-activated K＋ channels （SK channels） maintain the regularity and precision of firing by contributing to the afterhyperpolarization （AHP） of the action potential in mammals. However, it is not clear how SK channels regulate the output of the vocal motor system in songbirds. The premotor robust nucleus of the arcopallium （RA） in the zebra finch is responsible for the output of song information. The temporal pattern of spike bursts in RA projection neurons is associated with the timing of the acoustic features of birdsong. Methods The firing properties of RA projection neurons were analyzed using patch clamp whole-cell and cell-attached recording techniques. Results SK channel blockade by apamin decreased the AHP amplitude and increased the evoked firing rate in RA projection neurons. It also caused reductions in the regularity and precision of firing. RA projection neurons displayed regular spontaneous action potentials, while apamin caused irregular spontaneous firing but had no effect on the firing rate. In the absence of synaptic inputs, RA projection neurons still had spontaneous firing, and apamin had an evident effect on the firing rate, but caused no significant change in the firing regularity, compared with apamin application in the presence of synaptic inputs. Conclusion SK channels contribute to the maintenance of firing regularity in RA projection neurons which requires synaptic activity, and consequently ensures the precision of song encoding.
基金Project supported by the National Natural Science Foundation of China (Grant No.30900443)the Fundamental Research Funds for the Central Universities,China (Grant Nos.GK201302052 and GK261001007)
文摘Neurons in the brain utilize various firing trains to encode the input signals they have received. Firing behavior of one single neuron is thoroughly explained by using a bifurcation diagram from polarized resting to firing, and then to depolarized resting. This explanation provides an important theoretical principle for understanding neuronal biophysical behaviors. This paper reports the novel experimental and modeling results of the modification of such a bifurcation dia- gram by adjusting small conductance potassium （SK） channel. In experiments, changes in excitability and depolarization block in nucleus accumbens shell and medium-spiny projection neurons are explored by increasing the intensity of injected current and blocking the SK channels by apamin. A shift of bifurcation points is observed. Then, a Hodgkin-Huxley type model including the main electrophysiological processes of such neurons is developed to reproduce the experimental results. The reduction of SK channel conductance also shifts the bifurcations, which is in consistence with experiment. A global bifurcation paradigm of this shift is obtained by adjusting two parameters, intensity of injected current and SK channel con- ductance. This work reveals the dynamics underpinning modulation of neuronal firing behaviors by biologically important ionic conductance. The results indicate that small ionic conductance other than that responsible for spike generation can modify bifurcation points and shift the bifurcation diagram and, thus, change neuronal excitability and adaptation.
基金supported by the National Natural Science Foundation of China(31671054 and 81430024)the Postdoctoral Science Foundation of China(2017M610412)the Bureau of Science and Technology of Qingdao Municipality,China(17-1-1-44-jch)
文摘The pathogenesis of the second major neurodegenerative disorder, Parkinson’s disease(PD), is closely associated with the dysfunction of potassium(K~+ ) channels. Therefore, PD is also considered to be an ion channel disease or neuronal channelopathy. Mounting evidence has shown that K~+ channels play crucial roles in the regulations of neurotransmitter release, neuronal excitability, and cell volume. Inhibition of K~+ channels enhances the spontaneous firing frequency of nigral dopamine(DA)neurons, induces a transition from tonic firing to burst discharge, and promotes the release of DA in the striatum.Recently, three K~+ channels have been identified to protect DA neurons and to improve the motor and non-motor symptoms in PD animal models: small conductance(SK)channels, A-type K~+ channels, and KV7/KCNQ channels.In this review, we summarize the physiological and pharmacological effects of the three K~+ channels. We also describe in detail the laboratory investigations regarding K~+ channels as a potential therapeutic target for PD.
基金supported by the National Natural Science Foundation of China(Nos.81971943,81772196,31470264,81271820,30870789,and 30300117)the Stanley Foundation from the Stanley Medical Research Institute(SMRI),United States(No.06R-1366)We acknowledge the Medicine Research Center for Structural Biology of Wuhan University for providing the confocal microscopy(Leica-LCS-SP8-STED).
文摘The human endogenous retroviruses type W family envelope(HERV-W env)gene is located on chromosome 7q21-22.Our previous studies show that HERV-W env is elevated in schizophrenia and HERV-W env can increase cal-cium influx.Additionally,the 5-HTergie system and particularly 5-hydroxytryptamine(5-HT)receptors play a prominent role in the pathogenesis and treatment of schizophrenia.5-hydroxytryptamine receptor 4(5-HT4R)agonist can block calcium channels.However,the underlying relationship between HERV-W env and 5-HT4R in the etiology of schizophrenia has not been revealed.Here,we used enzyme-linked immunosorbent assay to detect the concentration of HERV-W env and 5-HT4R in the plasma of patients with schizophrenia and we found that there were decreased levels of 5-HT4R and a negative correlation between 5-HT4R and HERV-W env in schizophrenia.Overexpression of HERV-W env decreased the transcription and protein levels of 5-HT4R but increased small conductance Ca^(2+)-activated K^(+)type 2 channels(SK2)expression levels.Further studies revealed that HERV-w env could interact with 5-HT4R.Additionally,luciferase assay showed that an essential region(-364 to-176 from the transcription start site)in the SK2 promoter was required for HERV-W env-induced SK2 expression.Importantly,5-HT4R participated in the regulation of SK2 expression and promoter activity.Electrophysiological recordings suggested that HERV-Wenv could increase SK2 channel currents and the increase of SK2 currents was inhibited by 5-HT4R.In condusion,HERV-W env could activate SK2 channels via decreased 5-HT4R,which might exhibit a novel mechanism for HERV-Wenv to influence neuronal activity in schizophrenia.
