小鼠前额叶HCN通道在orexin A皮层兴奋性效应中的作用
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摘要
Orexin(又称hypocretin)是1998年发现的一类小分子神经肽,主要由外侧下丘脑区特定神经元产生。Orexin系统包括来源于同一前体分子的两个单体orexin A和orexin B,以及两种特异的G蛋白耦联受体OX1R和OX2R。Orexin系统与机体一系列生理功能的调控相关,目前认为其最重要的功能是对睡眠-觉醒的调节。前额叶皮层(prefrontal cortex, PFC)是大脑高级神经功能活动的中枢,其功能的顺利执行与其觉醒状态的维持密切相关。“超极化激活-环核苷酸门控的阳离子通道(hyperpolarization- activated cyclic nucleotide-gated channel,HCN channel)”位于前额叶皮层锥体神经元的树突,其开放引发“超极化激活的电流(hyperpolarization-activated currents,Ih)”。HCN通道参与树突信息整合过程,因此在前额叶皮层兴奋性的调控中发挥着重要的作用。目前已知多种神经递质和化学药物可以通过其对HCN通道的调控来影响或者改变神经元的兴奋性。促醒肽orexin A对前额叶皮层锥体神经元具有较强的兴奋性效应,而HCN通道是否也参与了orexin A这种兴奋性效应的产生和维持,目前尚未有文献报道。
本实验采用全细胞膜片钳记录技术,在课题组前期实验的基础上,首先观察HCN通道对小鼠前额叶皮层缘前区(the prelimbic area, PL) V层锥体细胞兴奋性的影响,然后进一步研究orexin A对Ih电流的影响,分析HCN通道在orexin A细胞兴奋性效应中的作用,并对其相应的细胞信号机制作初步的探讨。结果如下:
1. HCN通道参与PL区V层锥体神经元兴奋性的调节
电流钳模式下,注入一定剂量的内向电流,使记录细胞产生一定频率的自发性放电,给予HCN通道阻断剂ZD7288灌流给药后,记录细胞的放电频率明显加快;相反,给予8-Br-cAMP使Ih增大后,记录细胞的放电频率明显减慢。另外,在静息电位水平下,ZD7288使固定电流强度刺激下的动作电位发放数目显著增多;相反,给予8-Br-cAMP使动作电位发放数目显著减少。上述结果表明:HCN通道状态能够影响前额叶皮层神经元的兴奋性,即增强HCN通道活性可以降低神经元兴奋性,反之,抑制HCN通道活性则可以增加神经元兴奋性。
2. Orexin A的兴奋性效应与反应细胞Ih电流的产生具有密切关系
实验中,并非所有的PL区V层锥体神经元对orexin A均有反应,反应率为51.9%(28/54),根据细胞能否产生Ih电流,对反应阳性细胞作进一步的分类,结果发现:Ih (+)锥体神经元对orexin A的反应率为66.7%(24/36),远远高于Ih (-)锥体神经元对orexin A的反应率22.2%(4/18)(P<0.01),此结果强烈提示orexinA与Ih电流具有密切关系。
3. Orexin A对HCN通道具有抑制作用,该效应由OX1R介导,PKC参与
电流钳模式下,orexin A使反转电位“sag”明显减小,其中,“sag ratio”值由1.31±0.07下降到1.02±0.05(P<0.05, n=7)。电压钳模式下,orexin A使Ih电流幅值在各个跃阶电压水平均有减小,-120mv下最明显。另外,通过获得Ih电流激活曲线的“tail”电流图像,根据Boltzmann方程计算出每一电压水平下的Itail.max-Itail /Itail. max值,结果发现:orexin A使Ih电流激活曲线向超极化方向移动。上述结果表明:orexin A对HCN通道具有抑制作用。
电压钳模式下,重复前面的实验方式,给予OX1R阻断剂SB-334867,结果显示:给药前,orexin A使-120mv下的Ih电流下降到51.6±6.7pA;给药后,Ih电流恢复到75.4±8.2pA(P<0.05, n=3),将SB- 334867和orexin A冲洗置换后,Ih电流基本恢复到最大水平;给予PKC抑制剂BIS- II,结果显示:给药前,orexin A使Ih电流下降到原有幅值的52.6±4.8%,给药60min和90min后,Ih电流分别恢复到65.4±5.5% (P<0.05, n=7)和83.6±6.7%(P<0.01, n=5)。上述结果表明:OX1R和PKC参与介导orexin A对HCN通道的抑制作用。
4.HCN通道的状态影响orexin A的细胞兴奋性效应
电流钳模式下,先选择对orexin A具有明确兴奋性反应且具有典型Ih电流的PL区V层锥体神经元,然后给予8-Br-cAMP增强Ih电流,再次观察orexin A对记录细胞的兴奋性效应。结果显示:给药后,orexin A的兴奋性效应有所减弱,动作电位发放频率由5.83±0.45Hz下降到3.78±0.66Hz(P<0.05, n=4)。此结果表明HCN通道的状态能够影响orexin A的细胞兴奋性效应。
综上所述,本研究结果表明:第一,HCN通道参与PL区V层锥体神经元兴奋性的调节。第二,orexin A对HCN通道具有抑制作用,并且该效应由OX1R介导,PKC参与。第三,orexin A的兴奋性效应与反应细胞Ih电流的产生具有密切关系, HCN通道状态能够影响orexin A的细胞兴奋性效应。
Orexin (hypocretin) which mainly produced by the neurons within the lateral hypothalamus, is a micromolecular neuropeptide discovered in 1998. Orexin system includes two separate peptides orexin A and B proteolytically derived from the same precursor protein and two specific G-protein-coupled receptors OX1R and OX2R. Orexin system is relative with the regulation of many physiological functions, among these, its regulative role on“sleep-wake”is now considered to be most important. As we known, prefrontal cortex (PFC) plays an important role on execution of higher nervous activity, and its activity is correlated with level of wakefulness. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mainly locates on the dendritic spines of pyramidal neurons in PFC, inducing hyperpolarization -activated currents (Ih) when it is activated. HCN channel participate in the integration of excitatory synaptic input in pyramidal neurons, and thereby influences the excitability of neural network in PFC. Importantly, some transmitters and drugs can influence the neuronal excitability via regulation of HCN channels. Orexin A, as a classical wake-promoting neuropeptide, can enhance the activity of pyramidal neurons in prefrontal cortex effectively, while whether this effect of orexin A on prefrontal cortex pyramidal neurons involves its regulation on HCN currents is still little known.
In the present study, using whole-cell voltage-clamp recordings on layer V pyramidal neurons of mouse prelimbic cortex (PL), one important part of the medial prefrontal cortex, we firstly observed the regulation of HCN channel on neuronal excitability, and then the interaction between orexin A and HCN channel was studied systematically. The results show as follow:
1. HCN channels regulates the excitability of pyramidal neurons in PL of mice
The membrane potential was initially adjusted to-50 to -53mv using intracellular injection of direct current, and the recording neurons (n=6) fired spontaneously under this condition. Bath application of HCN channel blocker ZD7288 produced a modest depolarization in the membrane potential and dramatically increased spike firing. Adversely, the membrane potential was initially adjusted to -46 to -50mv in order that PL pyramidal neurons (n=5) fired at much higher frequency. Bath application of HCN channel enhancer 8-Br-cAMP dramatically decreased the spike firing. These data indicate that HCN channel can influence the excitability of pyramidal neurons in PFC. Increased HCN current decreases excitability, blockade of HCN channel enhances excitability.
2. Relation between the excitatory effect orexin A and the production Ih current on pyramidal neurons in PL
Not all recording pyramidal neurons in PL reacted to orexin A, the total reaction rate of orexinA on 54 recorded pyramid neurons was 51.9%, furthermore, the reaction rate of orexinA on 36 Ih (+) pyramid neurons was 66.7%, while the other18 Ih (-) pyramid neurons was 22.2%. These data indicate that the excitatory effect orexin A is much more noticeable in pyramid neurons with HCN channel.
3. Orexin A can suppress HCN channel in PL pyramid neurons, which is mediated by OX1R and PKC
In current-clamp model, applying orexinA produced a reduction of voltage sag in recording cells, and the voltage sag ratio induced by Ih current was significantly decreased after application of orexin A (from 1.31±0.09 to 1.08±0.07, P<0.05, n=7). In voltage -clamp model, orexin A produced a significant decrease in the amplitude of Ih current evoked by voltage ramp protocol, and the suppression of orexin A on Ih current displayed in almost all hyperpolarized voltage steps (I-V:-70~-120mv, n=14). In addition, the activation curve of Ih current which was calculated by using the equation Itail.max-Itail/Itail.max had a negative shift of the half-activation voltage (V1/2) from 84.7+/-1.1 to 92.2+/-2.7mV after applying orexin A.
The protocol was repeated in the presence of the OXR1 antagonist SB334867 and PKC inhibitor BIS-II. The amplitude of Ih current was decreased to 51.6±6.7 pA by 4 orexin A, and then recovered to 75.4±8.2pA by pre-application of SB334867 (P<0.05, n=3). Similarly, after bath incubation with BIS-II for from 30 to 90 minutes, the amplitude of Ih current respectively recovered to 65.4±5.5% at 60min point (P<0.05, n=7) and to 83.6±6.7% at 90min point (P<0.01, n=5). These data indicate that the role orexin A on HCN channel can be mediated by OXR1 and PKC.
4. The state of HCN channel influences excitatory effect of orexin A on PL pyramidal neurons
Firstly, the neurons which could be excited by orexin A effectively were selected. Then, 8-Br-cAMP was bathed in recording solution before orexin A application again. As result, the spike firing induced by orexinA was attenuated modestly compared with the former (from 5.83±0.45Hz; to 3.78±0.66Hz, P<0.05, n=4). This data indicate that the state of HCN channel can influence excitatory effect of orexin A on PL pyramidal neurons.
In summary, the studies reported here provide evidence that HCN channels have powerful influence on the firing properties of PL pyramidal neurons. Blockade of HCN channels increases the activity of PL pyramidal neurons, conversely, up-regulation of Ih current dramatically decreases the activity of PL pyramidal neurons. Most importantly, the present studies indicate that orexin A can decrease the amplitude of HCN currents and shift the currents activation curve to more negative level in PL pyramidal neurons, this effect is mediated by OX1 receptor and PKC signalling pathway. Furthermore, the excitatory effect of orexin A on PL pyramidal neurons is attenuated when HCN currents were enlarged.
本实验采用全细胞膜片钳记录技术,在课题组前期实验的基础上,首先观察HCN通道对小鼠前额叶皮层缘前区(the prelimbic area, PL) V层锥体细胞兴奋性的影响,然后进一步研究orexin A对Ih电流的影响,分析HCN通道在orexin A细胞兴奋性效应中的作用,并对其相应的细胞信号机制作初步的探讨。结果如下:
1. HCN通道参与PL区V层锥体神经元兴奋性的调节
电流钳模式下,注入一定剂量的内向电流,使记录细胞产生一定频率的自发性放电,给予HCN通道阻断剂ZD7288灌流给药后,记录细胞的放电频率明显加快;相反,给予8-Br-cAMP使Ih增大后,记录细胞的放电频率明显减慢。另外,在静息电位水平下,ZD7288使固定电流强度刺激下的动作电位发放数目显著增多;相反,给予8-Br-cAMP使动作电位发放数目显著减少。上述结果表明:HCN通道状态能够影响前额叶皮层神经元的兴奋性,即增强HCN通道活性可以降低神经元兴奋性,反之,抑制HCN通道活性则可以增加神经元兴奋性。
2. Orexin A的兴奋性效应与反应细胞Ih电流的产生具有密切关系
实验中,并非所有的PL区V层锥体神经元对orexin A均有反应,反应率为51.9%(28/54),根据细胞能否产生Ih电流,对反应阳性细胞作进一步的分类,结果发现:Ih (+)锥体神经元对orexin A的反应率为66.7%(24/36),远远高于Ih (-)锥体神经元对orexin A的反应率22.2%(4/18)(P<0.01),此结果强烈提示orexinA与Ih电流具有密切关系。
3. Orexin A对HCN通道具有抑制作用,该效应由OX1R介导,PKC参与
电流钳模式下,orexin A使反转电位“sag”明显减小,其中,“sag ratio”值由1.31±0.07下降到1.02±0.05(P<0.05, n=7)。电压钳模式下,orexin A使Ih电流幅值在各个跃阶电压水平均有减小,-120mv下最明显。另外,通过获得Ih电流激活曲线的“tail”电流图像,根据Boltzmann方程计算出每一电压水平下的Itail.max-Itail /Itail. max值,结果发现:orexin A使Ih电流激活曲线向超极化方向移动。上述结果表明:orexin A对HCN通道具有抑制作用。
电压钳模式下,重复前面的实验方式,给予OX1R阻断剂SB-334867,结果显示:给药前,orexin A使-120mv下的Ih电流下降到51.6±6.7pA;给药后,Ih电流恢复到75.4±8.2pA(P<0.05, n=3),将SB- 334867和orexin A冲洗置换后,Ih电流基本恢复到最大水平;给予PKC抑制剂BIS- II,结果显示:给药前,orexin A使Ih电流下降到原有幅值的52.6±4.8%,给药60min和90min后,Ih电流分别恢复到65.4±5.5% (P<0.05, n=7)和83.6±6.7%(P<0.01, n=5)。上述结果表明:OX1R和PKC参与介导orexin A对HCN通道的抑制作用。
4.HCN通道的状态影响orexin A的细胞兴奋性效应
电流钳模式下,先选择对orexin A具有明确兴奋性反应且具有典型Ih电流的PL区V层锥体神经元,然后给予8-Br-cAMP增强Ih电流,再次观察orexin A对记录细胞的兴奋性效应。结果显示:给药后,orexin A的兴奋性效应有所减弱,动作电位发放频率由5.83±0.45Hz下降到3.78±0.66Hz(P<0.05, n=4)。此结果表明HCN通道的状态能够影响orexin A的细胞兴奋性效应。
综上所述,本研究结果表明:第一,HCN通道参与PL区V层锥体神经元兴奋性的调节。第二,orexin A对HCN通道具有抑制作用,并且该效应由OX1R介导,PKC参与。第三,orexin A的兴奋性效应与反应细胞Ih电流的产生具有密切关系, HCN通道状态能够影响orexin A的细胞兴奋性效应。
Orexin (hypocretin) which mainly produced by the neurons within the lateral hypothalamus, is a micromolecular neuropeptide discovered in 1998. Orexin system includes two separate peptides orexin A and B proteolytically derived from the same precursor protein and two specific G-protein-coupled receptors OX1R and OX2R. Orexin system is relative with the regulation of many physiological functions, among these, its regulative role on“sleep-wake”is now considered to be most important. As we known, prefrontal cortex (PFC) plays an important role on execution of higher nervous activity, and its activity is correlated with level of wakefulness. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel mainly locates on the dendritic spines of pyramidal neurons in PFC, inducing hyperpolarization -activated currents (Ih) when it is activated. HCN channel participate in the integration of excitatory synaptic input in pyramidal neurons, and thereby influences the excitability of neural network in PFC. Importantly, some transmitters and drugs can influence the neuronal excitability via regulation of HCN channels. Orexin A, as a classical wake-promoting neuropeptide, can enhance the activity of pyramidal neurons in prefrontal cortex effectively, while whether this effect of orexin A on prefrontal cortex pyramidal neurons involves its regulation on HCN currents is still little known.
In the present study, using whole-cell voltage-clamp recordings on layer V pyramidal neurons of mouse prelimbic cortex (PL), one important part of the medial prefrontal cortex, we firstly observed the regulation of HCN channel on neuronal excitability, and then the interaction between orexin A and HCN channel was studied systematically. The results show as follow:
1. HCN channels regulates the excitability of pyramidal neurons in PL of mice
The membrane potential was initially adjusted to-50 to -53mv using intracellular injection of direct current, and the recording neurons (n=6) fired spontaneously under this condition. Bath application of HCN channel blocker ZD7288 produced a modest depolarization in the membrane potential and dramatically increased spike firing. Adversely, the membrane potential was initially adjusted to -46 to -50mv in order that PL pyramidal neurons (n=5) fired at much higher frequency. Bath application of HCN channel enhancer 8-Br-cAMP dramatically decreased the spike firing. These data indicate that HCN channel can influence the excitability of pyramidal neurons in PFC. Increased HCN current decreases excitability, blockade of HCN channel enhances excitability.
2. Relation between the excitatory effect orexin A and the production Ih current on pyramidal neurons in PL
Not all recording pyramidal neurons in PL reacted to orexin A, the total reaction rate of orexinA on 54 recorded pyramid neurons was 51.9%, furthermore, the reaction rate of orexinA on 36 Ih (+) pyramid neurons was 66.7%, while the other18 Ih (-) pyramid neurons was 22.2%. These data indicate that the excitatory effect orexin A is much more noticeable in pyramid neurons with HCN channel.
3. Orexin A can suppress HCN channel in PL pyramid neurons, which is mediated by OX1R and PKC
In current-clamp model, applying orexinA produced a reduction of voltage sag in recording cells, and the voltage sag ratio induced by Ih current was significantly decreased after application of orexin A (from 1.31±0.09 to 1.08±0.07, P<0.05, n=7). In voltage -clamp model, orexin A produced a significant decrease in the amplitude of Ih current evoked by voltage ramp protocol, and the suppression of orexin A on Ih current displayed in almost all hyperpolarized voltage steps (I-V:-70~-120mv, n=14). In addition, the activation curve of Ih current which was calculated by using the equation Itail.max-Itail/Itail.max had a negative shift of the half-activation voltage (V1/2) from 84.7+/-1.1 to 92.2+/-2.7mV after applying orexin A.
The protocol was repeated in the presence of the OXR1 antagonist SB334867 and PKC inhibitor BIS-II. The amplitude of Ih current was decreased to 51.6±6.7 pA by 4 orexin A, and then recovered to 75.4±8.2pA by pre-application of SB334867 (P<0.05, n=3). Similarly, after bath incubation with BIS-II for from 30 to 90 minutes, the amplitude of Ih current respectively recovered to 65.4±5.5% at 60min point (P<0.05, n=7) and to 83.6±6.7% at 90min point (P<0.01, n=5). These data indicate that the role orexin A on HCN channel can be mediated by OXR1 and PKC.
4. The state of HCN channel influences excitatory effect of orexin A on PL pyramidal neurons
Firstly, the neurons which could be excited by orexin A effectively were selected. Then, 8-Br-cAMP was bathed in recording solution before orexin A application again. As result, the spike firing induced by orexinA was attenuated modestly compared with the former (from 5.83±0.45Hz; to 3.78±0.66Hz, P<0.05, n=4). This data indicate that the state of HCN channel can influence excitatory effect of orexin A on PL pyramidal neurons.
In summary, the studies reported here provide evidence that HCN channels have powerful influence on the firing properties of PL pyramidal neurons. Blockade of HCN channels increases the activity of PL pyramidal neurons, conversely, up-regulation of Ih current dramatically decreases the activity of PL pyramidal neurons. Most importantly, the present studies indicate that orexin A can decrease the amplitude of HCN currents and shift the currents activation curve to more negative level in PL pyramidal neurons, this effect is mediated by OX1 receptor and PKC signalling pathway. Furthermore, the excitatory effect of orexin A on PL pyramidal neurons is attenuated when HCN currents were enlarged.
引文
1. de Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. PNAS, 1998, 95(1):322-327
2. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 1998, 92(4): 573-585
3. Zhu Y, Miwa Y, Yamanaka A, et al. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussiss toxin-sensitive and–insensitive G-proteins. J Pharmacol Sci, 2003, 92(3): 259-266
4. Nishino S. The hypothalamic peptidergic system, hypocretin/orexin and vigilance control. Neuropeptides, 2007, 41(3):117-133
5. Antoine R Adamantidis, Feng Zhang, Alexander M Aravanis, et al. Neural substrates ofawakening probed with optogenetic control of hypocretin neurons. Nature, 2007, 450(7168):420-424
6. Ohno K, Sakurai T. Orexin neuronal circuitry: role in the regulation of sleep and wakefulness[J]. Front Neuroendocrinol, 2008, 29(1):70-87
7. Hoang QV, Bajic D, Yanagisawa M, et al. Orexin (hypocretin) effects on GIRK channels. J Neurophysiol, 2003, 90(2): 693-702
8. Liu RJ, Van Den Pol AN. and Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci, 2002, 22(21): 9453-9464
9. Taylor MM and Samson WK. The other side of the orexin: Endocrein and metabolic actions. Am J Physiol Endocrinol Metab, 2003, 284(1): E13-E17
10. Jones BE. Arousal systems. Front Biosci, 2003, 8: s438-51
11.宋承辉,胡志安. Orexin:觉醒通路中一种重要的下丘脑神经肽.第三军医大学学报,2003,25(13):1207-1209
12. Lu XY, Bagnol D, Burke S, et al. Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav, 2000, 37:335–344.
13. Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol, 2001, 435(1):6-25.
14. Xia J, Chen X, Song C, et al. Postsynaptic excitation of prefrontal cortical pyramidal neurons by hypocretin-1/orexin A through the inhibition of potassium currents. J Neurosci Res, 2005, 82:729-736
15. Xu R, Wang Q, Yan M, et al. Orexin-A augments voltage-gated Ca2+ currents and synergistically increases growth hormone (GH) secretion with GH-releasing hormone in primary cultured ovine somatotropes. Endocrinology, 2002, 143(12): 4609-4619
16. Burdakov D, Liss B and Ashcroft FM. Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium-calcium exchanger. J Neurosci, 2003, 23(12): 4951-4957
17. Larsson KP, Peltonen HM, Bart G, et al. Orexin-A-induced Ca2+ entry: evidence for involvement of trpc channels and protein kinase C regulation. J Biol Chem, 2005, 280(3):1771-1781
18. Yang B, Samson WK, Ferguson AV, et al. Excitatory effects of orexin A on nucleutractus solitarius neurons are mediated by phospholipase C and protein kinase C. J Neurosci, 2003,23(15):6215-6222
19. Murai Y and Akaike T. Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons. Neurosci Res , 2005, 51(1):55-65
20. Day M, Carr DB, Ulrich S, et al. Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci, 2005, 25:8776-87.
21. Carr DB, Andrews GD, Glen WB, et al.α2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584: 437–450.
22. Wang M, Ramos BP, Paspalas CD, et al.α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP HCN channel signaling in prefrontal cortex. Cell, 2007, 129:397–410.
23. Arnsten AF. Catecholamine and Second Messenger Influences on Prefrontal Cortical Networks of‘‘Representational Knowledge’’: A Rational Bridge between Genetics and the Symptoms of Mental Illness. Cerebral Cortex, 2007, 17 (supplement):i6--i15.
24. Robinson RB, Siegelbaum SA. HYPERPOLARIZATION-ACTIVATED CATION CURRENTS: From Molecules to Physiological Function. Annu Rev Physiol, 2003, 65:453–480
25.岳鑫,王均辉,秦绿叶,等. HCN通道在神经系统中的功能和作用.生理科学进展, 2008, 39(3):247-250
26. Notomi T and Shigemoto R. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J. Comp. Neurol, 2004, 471:241–276
27. Nusser Z. Variability in the subcellular distribution of ion channels increases neuronal diversity. Trends Neurosci., 2009 [Epub ahead of print]
28. Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci,1998, 18:7613–7624.
29. Santoro, B, Chen, S, Luthi, A., et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J Neurosci, 2000, 20:5264–5275
30. Lorincz, A., Notomi, T., Tamas, G.., et al. Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat. Neurosci 5, 2002: 1185–1193
31. Yu X, Duan KL, Shang CF, et al. Calcium influx through hyperpolarization-activated cation channels (Ih channels) contributes to activity-evoked neuronal secretion. Proc Natl Acad Sci U S A., 2004, 101:1051-1056
32. Magee, J.C. Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci, 1999, 2:508–514
33. Williams SR and Stuart GJ. Role of dendritic synapse location in the control of action potential output. TRENDS in Neurosciences, 2003, 26:147-154
34. Hysell Oviedo, Alex D. Reyes Variation of Input–Output Properties along the Somatodendritic Axis of Pyramidal Neurons. J. Neurosci, 2005, 25:4985– 4995
35. Minyoung Shin, and Dane M. Chetkovich. Activity-dependent regulation of h channel distribution in hippocampal CA1 pyramidal neurons. J Biol Chem, 2007, 282(45):33168-33180
36. Tsay D, Dudman JT, Siegelbaum SA. HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons. Neuron, 2007, 56(6): 1076-1089
37. Williams SR, Wozny C, Mitchell SJ. The back and forth of dendritic plasticity. Neuron, 2007, 56(6): 947-953
38. Bender RA, Soleymani SV, Brewster AL, et al. Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus. J Neurosci, 2003, 23(17): 6826-6836
39. Poolos N P. The Yin and Yang of the H-Channel and Its Role in Epilepsy. Epilepsy Curr, 2004, 4(1):3-6
40. Schweitzer P, Madamba S G, Siggins G R.The sleep-modulating peptide cortistatin augments the h-current in hippocampal neurons. J Neurosci, 2003, 23(34):10884–10891
41. Harry BM Uylings, Henk J Groenewegen, Bryan Kolb. Do rats have a prefrontal cortex. Behavioural Brain Research, 2003, 146(1-2):3–17
42. Vertes RP. Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat. Neuroscience, 2006, 142(1):1-20
43. Heidbreder CA, Groenewegen HJ. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev, 2003, 27(6):555-79
44. Passetti F, Levita L, Robbins TW. Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions. Behav Brain Res, 2003, 138(1):59–69
45. Delatour B, Gisquet-Verrier P. Functional role of rat prelimbic–infralimbic cortices isspatial memory: evidence for their involvement in attention and behavioural flexibility. Behav Brain Res, 2000, 109(1):113–28
46. Jones MW. A comparative review of rodent prefrontal cortex and working memory. Curr Mol Med, 2002, 2(7):639-647
47. Harry BM Uylings, Henk J Groenewegen, Bryan Kolb. Do rats have a prefrontal cortex? Behavioural Brain Research, 2003, 146(1-2):3–17
48. Dégenètais E, Thierry A M, Glowinski J, et al. Electrophysiological properties of pyramidal neurons in the rat prefrontal cortex: an in vivo intracellular recording study. Cereb Cortex, 2002, 12(1):1-16
49. Destexhe A, Contreras D, Steriade M, et al. In vivo, in vitro, and computational analysis of dendritic calcium currents in thalamic reticular neurons. J Neurosci, 1996, 16,:169–185
50. Franz O, Liss B, Neu A, et al. Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarizationactivated cyclic nucleotide-gated ion channels (Ih) in central neurons. Eur J Neurosci, 2000, 12: 2685–2693
51. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 2001, 30 :345–354.
52. Chen S, Wang J, Siegelbaum SA. Properties of hyperpolarizationactivated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J Gen Physiol, 2001, 117:491–504
53. Wang J, Chen S, Siegelbaum SA. Regulation of hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions. J Gen Physiol, 2001, 118:237–250.
1. Rosenkranz J A, Johnston D. Dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex. J Neurosci, 2006, 26(12):3229-3244
2. Wang M, Ramos B P, Paspalas C D, et al.α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell, 2007, 129(2):397–410
3. Poolos N P. The Yin and Yang of the H-Channel and Its Role in Epilepsy. Epilepsy Curr,2004,4(1):3-6
4. Schweitzer P, Madamba S G, Siggins G R.The sleep-modulating peptide cortistatin augments the h-current in hippocampal neurons. J Neurosci, 2003, 23(34):10884–10891
5. Xia J, Chen X, Song C, et al. Postsynaptic excitation of prefrontal cortical pyramidal neurons by hypocretin-1/orexin A through the inhibition of potassium currents. J Neurosci Res, 2005, 82:729-736
6. Cathala L., Paupardin-Tritsch D. Neurotensin inhibition of the yperpolarization- activated cation current (Ih) in the rat substantia nigrapars compacta implicates the protein kinase C pathway. J Physiol (Lond), 1997, 503:87–97
7. LiuZ,BunneyEB, Appel SB, Brodie MS.Serotonin Reduces the Hyperpolarization- Activated Current (Ih) in VentralTegmental Area Dopamine Neurons: nvolvement of 5-HT2 Receptors and Protein Kinase C. J Neurophysio, 2003 90: 3201–3212
8. Brager DH, Johnston D. Plasticity of Intrinsic Excitability during Long-Term Depression Is Mediated through mGluR-Dependent Changes in Ih in Hippocampal CA1 Pyramidal Neurons. J Neurosci, 2007, 27:13926–13937.
9. Robinson RB, Siegelbaum SA. HYPERPOLARIZATION-ACTIVATED CATION CURRENTS: From Molecules to Physiological Function. Annu Rev Physiol, 2003, 65:453–480
10. Carr DB, Andrews GD, Glen WB, et al.α2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584: 437–450
11. Day M, Carr DB, Ulrich S, et al. Dendritic excitability of mouse frontal cortexpyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci, 2005, 25:8776-87
12. Franz O, Liss B, Neu A, et al. Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarizationactivated cyclic nucleotide-gated ion channels (Ih) in central neurons. Eur J Neurosci, 2000, 12: 2685–2693
13. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 2001, 30 :345–354
14. Biel M. Cyclic Nucleotide-regulated Cation Channels. J Biol Chem, 2009, 284(14):9017-21
15. Shah BH and Catt KJ. GPCR-mediated transactivation of RTKs in the CNS: mechanisms and consequences. Trends Neurosci, 2004, 27, 48–53
16. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 1999, 98: 437–451
17. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 2001, 30 :345–354
18. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med, 2001, 6:991–997
19. Hofle N, Paus T, Reutens D, et al. Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans. J Neurosci, 1997, 17:4800–4808
20. Paus T, Koski L, Caramanos Z, Westbury C. Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex: a review of 107 PET activation studies. Neuroreport, 1998, 9:R37–47
21. Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res, 2000, 9:335–352
22. Lambe EK, Aghajanian GK. Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron, 2003, 40:139–150.
23. Naumann, A., Bierbrauer, J., Przuntek, H., et al. Attentive and preattentive processingin narcolepsy as revealed by event related potentials (ERPs). Neuroreport, 2001, 12, 2807–2811
24. Rieger, M., Mayer, G., and Gauggel, S. Attention deficits in patients with narcolepsy. Sleep, 2003, 26, 36–43
25. Mishima K, Fujiki N, Yoshida Y, et al. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. Sleep, 2008, 31:1119-1126
26. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 1998, 92:573–585
27. Arnsten AF. Catecholamine and Second Messenger Influences on Prefrontal Cortical Networks of‘‘Representational Knowledge’’: A Rational Bridge between Genetics and the Symptoms of Mental Illness. Cerebral Cortex, 2007, 17 (supplement):i6--i15
28. Wang M, Ramos BP, Paspalas CD, et al.α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP HCN channel signaling in prefrontal cortex. Cell, 2007, 129:397–410
29. Hoang QV, Bajic D, Yanagisawa M, et al. Orexin (hypocretin) effects on GIRK channels. J Neurophysiol, 2003, 90(2): 693-702
30. Taheri S, Zeitzer JM, Mignot E. The role of hyocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci, 2002;25:283-313
31. Foote SL, Aston-Jones G, Bloom FE. Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc Natl Acad Sci USA, 1980, 77: 3033—3037
32. Chen XW, Mu Y, Huang HP, et al. Hypocretin-1 potentiates NMDA receptor-mediated somatodendritic secretion from locus coeruleus neurons. J. Neurosci., 2008, 28:3202-08
33. Tanabe M. Inhibition of hyperpolarization-activated cation currents by phencyclidine and some sigma ligands in rat hippocampal CA1 pyramidal neurons in vitro. Neuropharmacology, 2007, 53: 406-414.
34. Nishino S. The hypothalamic peptidergic system, hypocretin/orexin and vigilance control. Neuropeptides, 2007, 41:117-133
1. Noma A, Irisawa H. Membrane currents in the rabbit sinoatrial node cell a studied by the double microelectrode method. Pfl¨ugers Arch., 1976, 364:45–52
2. Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature, 1979, 280:235–36
3. Halliwell JV, Adams PR. Voltageclamp analysis of muscarinic excitation in hippocampal neurons. Brain Res, 1982, 250:71–92
4. Chen S, Wang J, Siegelbaum SA. Properties of hyperpolarization-activated pacemaker current defined by coassembly of hcn1 and hcn2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol., 2001, 117:491–504
5. Wainger BJ, DeGennaro M, Santoro B, et al. Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature, 2001, 411:805–10
6. Wahl-Schott C, Biel M. HCN channels: structure, cellular regulation and physiological function. Cell Mol Life Sci, 2009, 66(3):470-94
7. Santoro B, Tibbs GR.The HCN gene family: molecular basis of the hyperpolar ization-activated pacemaker channels. Ann. NY Acad. Sci., 1999, 868:741–64
8. Ulens, C. and Tytgat, J. Functional heteromerization of HCN1 and HCN2 pacemaker channels. J. Biol. Chem, 2001, 276, 6069–6072
9. Xue, T., Marban, E. and Li, R. A. Dominant-negative suppression of HCN1- and HCN2-encoded pacemaker currents by an engineered HCN1 construct: insights into structure-function relationships and multimerization. Circ. Res. 2002, 90, 1267–1273
10. Altomare, C., Terragni, B., Brioschi, C., et al. Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node. J. Physiol, 2003, 549, 347–359
11. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol., 1993, 55:455–72
12. Raman IM, Bean BP. Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J. Neurosci., 1999,19:1663–74
13. Thoby-Brisson M, Telgkamp P, Ramirez JM. The role of the hyperpolarization- activated current in modulating rhythmic activity in the isolated respiratory network ofmice. J. Neurosci., 2000, 20:2994–3005
14. Irisawa H, Brown HF, GilesW. Cardiac pacemaking in the sinoatrial node. Physiol. Rev, 1993, 73:197–227
15. Noma A, Morad M, Irisawa H. Does the“pacemaker current”generate the diastoli c depolarization in the rabbit SA node cells? Pfl¨ugers Arch., 1983, 397:190–94
16. Vassalle M. Cardiovascular controversies: The pacemaker current, if, does not play an important role in regulating SA node pacemaker activity. Cardiovasc., Res. 1995, 30:309–10
17. Robinson R B, Siegelbaum S A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol, 2003, 65:453-480
18. Kaupp, U. B. and Seifert, R. Cyclic nucleotide-gated ion channels. Physiol. Rev, 2002, 82, 769–824
19. Craven, K. B. and Zagotta, W. N. CNG and HCN channels: two peas, one pod. Annu. Rev. Physiol., 2006,68, 375–401
20. Biel, M. and Michalakis, S. Function and dysfunction of CNG channels: insights from channelopathies and mouse models. Mol. Neurobiol., 2007, 35, 266–277
21. Luthi A, McCormick DA. Hcurrent: properties of a neuronal and network pacemaker. Neuron, 1998, 21:9–12
22. Bal T, McCormick DA.Synchronized oscillations in the inferior olive are control- led by the hyperpolarizationactivated cation current I(h). J. Neurophysiol., 1997, 77:3145–56
23. Maccaferri G, McBain CJ. The hyperpolarization-activated current (Ih) and its contribution to pacemaker activity in rat CA1 hippocampal stratum oriensalveus interneurones. J. Physiol., 1996, 497(Pt.1):119–30
24. Gasparini S, DiFrancesco D. Action of the hyperpolarization-activated current (Ih) blocker ZD 7288 in hippocampal CA1 neurons. Pfl¨ugers Arch, 1997, 435:99–10
25. Shin KS, Rothberg BS, Yellen G.. Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate. J. Gen. Physiol, 2001, 117:91–101
26. DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature, 1991, 351:145–47
27. Ludwig A, Zong X, Jeglitsch M, Hofmann F, Biel M. A family of hyperpolar ization-activated mammalian cation channels. Nature, 1998, 393:587–91
28. Wang M, Ramos BP, Paspalas CD, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell, 2007; 129(2): 397-410
29. Bickmeyer U, Heine M, et al . Differential modulation of Ih by 5-HT receptors in mouse CA1 hippocampal neurons.Euro J Neurosci, 2002, (16):209-218
30. Vargas G, Lucero MT. Dopamine modulates inwardly rectifying Hyperpolar ization -activated current (Ih) in cultured rat olfactory receptor neurons. J Neurophysiol, 1999, 81(1): 149-158
31. Santoro, B., Grant, S.G., Bartsch,D.et al. Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proc. Natl. Acad. Sci. USA, 1997, 94,14815–14820
32. Santoro, B., Chen, S., Luthi, A., et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J. Neurosci, 2000,20, 5264–5275
33. Moosmang, S., Biel, M., Hofmann, F. et al. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol. Chem, 1999, 380, 975–980
34. Notomi, T. and Shigemoto, R. Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain. J. Comp. Neurol, 2004, 471, 241–276
35. MannikkoR, Elinder F, LarssonHP. Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages. Nature, 2002, 419:837–41
36. Rothberg BS, Shin KS, Phale PS, et al.Voltage-controlled gating at the intrace- llular entrance to a hyperpolarization-activated cation channel. J. Gen. Physiol, 2002, 119:83–91
37. Sanguinetti MC, Xu QP.Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes. J. Physiol,1999, 514 (Pt. 3): 667–75
38. Chen J, Mitcheson JS, Tristani-Firouzi M, et al.The S4-S5 linker couples voltage sensing and activation of pacemaker channels. Proc. Natl. Acad. Sci. USA, 2001,98:11277–82
39. Golgi, C. (1989) On the structure of nerve cells. 1898. J. Microsc. 155, 3–7
40. Ramon y Cajal, S. (1911) Histologie du systeme nerveux de l’homme et des vertebres. Maloine
41. Migliore, M. and Shepherd, G.M. Emerging rules for the distribution of active dendritic conductances. Nat. Rev. Neurosci, 2002, 3, 362–370
42. Williams, S.R. and Stuart, G.J. Role of dendritic synapse location in the control of action potential output. Trends Neurosci, 2003, 26, 147–154
43. Magee, J.C. and Johnston, D. Plasticity of dendritic function. Curr. Opin. Neurobiol, 2005,15, 334–342
44. Lai, H.C. and Jan, L.Y. The distribution and targeting of neuronal voltage-gated ion channels. Nat. Rev. Neurosci, 2006, 7, 548–562
45. Spruston, N. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci, 2008, 9, 206–221
46. Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci, 1998, 18: 7613– 7624
47. Lorincz, A., Notomi, T., Tamas, G., et al Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat. Neurosci , 2002, 5: 1185–1193
48. Berger T, Larkum ME, Luscher H-R. High Ih channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. J Neurophysiol, 2001, 85, 855–868
49. Lujan, R., Albasanz, J.L., Shigemoto, R. et al. Preferential localization of the hyperpolarization-activated cyclic nucleotide-gated cation channel subunit HCN1 in basket cell terminals of the rat cerebellum. Eur J Neurosci ,2005,21, 2073-2082
50. Aponte, Y., Lien, C., Reisinger, E. and Jonas, P. Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus. J Physiol, 2006, 574, 229-243
51. Brewster, A.L., Chen, Y., Bender, R.A., et al. Quantitative analysis and subcellular distribution of mRNA and protein expression of the hyperpolarization-activated cyclic nucleotide-gated channels throughout development in rat hippocampus. Cereb Cortex, 2007, 17, 702-712
52. Cuttle, M.F., Rusznak, Z., Wong, A.Y., Owens, S. and Forsythe, I.D. Modulation of a presynaptic hyperpolarization-activated cationic current (I(h)) at an excitatory synaptic terminal in the rat auditory brainstem. J Physiol, 2001, 534, 733-744
53. Soleng, A.F., Chiu, K. and Raastad, M. Unmyelinated axons in the rat hippocam- pus hyperpolarize and activate an H current when spike frequency exceeds 1 Hz. J Physiol, 2003, 552, 459-470
54. Bender, R.A., Kirschstein, T., Kretz, O., et al. () Localization of HCN1 channels to presynaptic compartments: novel plasticity that may contribute to hippocampal maturation. J Neurosci, 2007, 27, 4697-4706
55. Nicoll A, Larkman A, Blakemore C. Modulation of EPSP shape and efficacy by intrinsic membrane conductances in rat neocortical pyramidal neurons in vitro. J. Physiol, 1993, 468:693–710
56. Magee JC. Dendritic lh normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci, 1999, 2:508–14
57. Williams SR, Stuart GJ. Site independence of EPSP time course is mediated by dendritic I(h) in neocortical pyramidal neurons. J. Neurophysiol, 2000,83:3177–82
58. Fernandez N, Andreasen M, Nedergaard S. Influence of the hyperpolarization- activated cation current, I(h), on the electrotonic properties of the distal apical dendrites of hippocampal CA1 pyramidal neurones. Brain Res, 2002, 930:42–52
59. Poolos NP, Migliore M, Johnston D. 2002. Pharmacological upregulation of hchannels reduces the excitability of pyramidal neuron dendrites. Nat. Neurosci. 5:767–74
60. Buzsaki G.. Theta oscillations in the hippocampus. Neuron, 2002, 33:325–40
61. Staubli U, Lynch G.. Stable hippocampal long-term potentiation elicited by‘theta’pattern stimulation. Brain Res, 1987, 435:227–34
62. Leung LS,YuHW. Theta-frequency resonance in hippocampal CA1 neurons in vitro demonstrated by sinusoidal current injection. J. Neurophysiol, 1998, 79: 1592–96
63. Pike FG, Goddard RS, Suckling JM, et al. Distinct frequency preferences of different types of rat hippocampal neurones in response to oscillatory input currents. J. Physiol, 2000, 529(Pt. 1):205–13
64. Ulrich D. Dendritic resonance in rat neocortical pyramidal cells. J. Neurophysiol, 2002, 87:2753–59
65. Arnsten, A. F. Catecholamine and second messenger influences on prefrontal cortical networks of”representational knowledge”: a rational bridge between genetics and the symptoms ofmental illness.Cereb.Cortex, 2007, 17, i6–15
66. Vijayraghavan, S.,Wang, M., Birnbaum, et al.Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat. Neurosci, 2007, 10, 376–384
67. Williams, G. V. and Goldman-Rakic, P. S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature, 1995, 376, 572–575
68. Arnsten, A. F. Through the looking glass: differential noradenergic modulation of prefrontal cortical function. Neural. Plast, 2000, 7, 133–146
69. Carr DB, Andrews GD, Glen WB, et al.α2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584: 437–450
2. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 1998, 92(4): 573-585
3. Zhu Y, Miwa Y, Yamanaka A, et al. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussiss toxin-sensitive and–insensitive G-proteins. J Pharmacol Sci, 2003, 92(3): 259-266
4. Nishino S. The hypothalamic peptidergic system, hypocretin/orexin and vigilance control. Neuropeptides, 2007, 41(3):117-133
5. Antoine R Adamantidis, Feng Zhang, Alexander M Aravanis, et al. Neural substrates ofawakening probed with optogenetic control of hypocretin neurons. Nature, 2007, 450(7168):420-424
6. Ohno K, Sakurai T. Orexin neuronal circuitry: role in the regulation of sleep and wakefulness[J]. Front Neuroendocrinol, 2008, 29(1):70-87
7. Hoang QV, Bajic D, Yanagisawa M, et al. Orexin (hypocretin) effects on GIRK channels. J Neurophysiol, 2003, 90(2): 693-702
8. Liu RJ, Van Den Pol AN. and Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci, 2002, 22(21): 9453-9464
9. Taylor MM and Samson WK. The other side of the orexin: Endocrein and metabolic actions. Am J Physiol Endocrinol Metab, 2003, 284(1): E13-E17
10. Jones BE. Arousal systems. Front Biosci, 2003, 8: s438-51
11.宋承辉,胡志安. Orexin:觉醒通路中一种重要的下丘脑神经肽.第三军医大学学报,2003,25(13):1207-1209
12. Lu XY, Bagnol D, Burke S, et al. Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav, 2000, 37:335–344.
13. Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol, 2001, 435(1):6-25.
14. Xia J, Chen X, Song C, et al. Postsynaptic excitation of prefrontal cortical pyramidal neurons by hypocretin-1/orexin A through the inhibition of potassium currents. J Neurosci Res, 2005, 82:729-736
15. Xu R, Wang Q, Yan M, et al. Orexin-A augments voltage-gated Ca2+ currents and synergistically increases growth hormone (GH) secretion with GH-releasing hormone in primary cultured ovine somatotropes. Endocrinology, 2002, 143(12): 4609-4619
16. Burdakov D, Liss B and Ashcroft FM. Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium-calcium exchanger. J Neurosci, 2003, 23(12): 4951-4957
17. Larsson KP, Peltonen HM, Bart G, et al. Orexin-A-induced Ca2+ entry: evidence for involvement of trpc channels and protein kinase C regulation. J Biol Chem, 2005, 280(3):1771-1781
18. Yang B, Samson WK, Ferguson AV, et al. Excitatory effects of orexin A on nucleutractus solitarius neurons are mediated by phospholipase C and protein kinase C. J Neurosci, 2003,23(15):6215-6222
19. Murai Y and Akaike T. Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons. Neurosci Res , 2005, 51(1):55-65
20. Day M, Carr DB, Ulrich S, et al. Dendritic excitability of mouse frontal cortex pyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci, 2005, 25:8776-87.
21. Carr DB, Andrews GD, Glen WB, et al.α2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584: 437–450.
22. Wang M, Ramos BP, Paspalas CD, et al.α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP HCN channel signaling in prefrontal cortex. Cell, 2007, 129:397–410.
23. Arnsten AF. Catecholamine and Second Messenger Influences on Prefrontal Cortical Networks of‘‘Representational Knowledge’’: A Rational Bridge between Genetics and the Symptoms of Mental Illness. Cerebral Cortex, 2007, 17 (supplement):i6--i15.
24. Robinson RB, Siegelbaum SA. HYPERPOLARIZATION-ACTIVATED CATION CURRENTS: From Molecules to Physiological Function. Annu Rev Physiol, 2003, 65:453–480
25.岳鑫,王均辉,秦绿叶,等. HCN通道在神经系统中的功能和作用.生理科学进展, 2008, 39(3):247-250
26. Notomi T and Shigemoto R. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J. Comp. Neurol, 2004, 471:241–276
27. Nusser Z. Variability in the subcellular distribution of ion channels increases neuronal diversity. Trends Neurosci., 2009 [Epub ahead of print]
28. Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci,1998, 18:7613–7624.
29. Santoro, B, Chen, S, Luthi, A., et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J Neurosci, 2000, 20:5264–5275
30. Lorincz, A., Notomi, T., Tamas, G.., et al. Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat. Neurosci 5, 2002: 1185–1193
31. Yu X, Duan KL, Shang CF, et al. Calcium influx through hyperpolarization-activated cation channels (Ih channels) contributes to activity-evoked neuronal secretion. Proc Natl Acad Sci U S A., 2004, 101:1051-1056
32. Magee, J.C. Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci, 1999, 2:508–514
33. Williams SR and Stuart GJ. Role of dendritic synapse location in the control of action potential output. TRENDS in Neurosciences, 2003, 26:147-154
34. Hysell Oviedo, Alex D. Reyes Variation of Input–Output Properties along the Somatodendritic Axis of Pyramidal Neurons. J. Neurosci, 2005, 25:4985– 4995
35. Minyoung Shin, and Dane M. Chetkovich. Activity-dependent regulation of h channel distribution in hippocampal CA1 pyramidal neurons. J Biol Chem, 2007, 282(45):33168-33180
36. Tsay D, Dudman JT, Siegelbaum SA. HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons. Neuron, 2007, 56(6): 1076-1089
37. Williams SR, Wozny C, Mitchell SJ. The back and forth of dendritic plasticity. Neuron, 2007, 56(6): 947-953
38. Bender RA, Soleymani SV, Brewster AL, et al. Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus. J Neurosci, 2003, 23(17): 6826-6836
39. Poolos N P. The Yin and Yang of the H-Channel and Its Role in Epilepsy. Epilepsy Curr, 2004, 4(1):3-6
40. Schweitzer P, Madamba S G, Siggins G R.The sleep-modulating peptide cortistatin augments the h-current in hippocampal neurons. J Neurosci, 2003, 23(34):10884–10891
41. Harry BM Uylings, Henk J Groenewegen, Bryan Kolb. Do rats have a prefrontal cortex. Behavioural Brain Research, 2003, 146(1-2):3–17
42. Vertes RP. Interactions among the medial prefrontal cortex, hippocampus and midline thalamus in emotional and cognitive processing in the rat. Neuroscience, 2006, 142(1):1-20
43. Heidbreder CA, Groenewegen HJ. The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev, 2003, 27(6):555-79
44. Passetti F, Levita L, Robbins TW. Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions. Behav Brain Res, 2003, 138(1):59–69
45. Delatour B, Gisquet-Verrier P. Functional role of rat prelimbic–infralimbic cortices isspatial memory: evidence for their involvement in attention and behavioural flexibility. Behav Brain Res, 2000, 109(1):113–28
46. Jones MW. A comparative review of rodent prefrontal cortex and working memory. Curr Mol Med, 2002, 2(7):639-647
47. Harry BM Uylings, Henk J Groenewegen, Bryan Kolb. Do rats have a prefrontal cortex? Behavioural Brain Research, 2003, 146(1-2):3–17
48. Dégenètais E, Thierry A M, Glowinski J, et al. Electrophysiological properties of pyramidal neurons in the rat prefrontal cortex: an in vivo intracellular recording study. Cereb Cortex, 2002, 12(1):1-16
49. Destexhe A, Contreras D, Steriade M, et al. In vivo, in vitro, and computational analysis of dendritic calcium currents in thalamic reticular neurons. J Neurosci, 1996, 16,:169–185
50. Franz O, Liss B, Neu A, et al. Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarizationactivated cyclic nucleotide-gated ion channels (Ih) in central neurons. Eur J Neurosci, 2000, 12: 2685–2693
51. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 2001, 30 :345–354.
52. Chen S, Wang J, Siegelbaum SA. Properties of hyperpolarizationactivated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J Gen Physiol, 2001, 117:491–504
53. Wang J, Chen S, Siegelbaum SA. Regulation of hyperpolarization-activated HCN channel gating and cAMP modulation due to interactions of COOH terminus and core transmembrane regions. J Gen Physiol, 2001, 118:237–250.
1. Rosenkranz J A, Johnston D. Dopaminergic regulation of neuronal excitability through modulation of Ih in layer V entorhinal cortex. J Neurosci, 2006, 26(12):3229-3244
2. Wang M, Ramos B P, Paspalas C D, et al.α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell, 2007, 129(2):397–410
3. Poolos N P. The Yin and Yang of the H-Channel and Its Role in Epilepsy. Epilepsy Curr,2004,4(1):3-6
4. Schweitzer P, Madamba S G, Siggins G R.The sleep-modulating peptide cortistatin augments the h-current in hippocampal neurons. J Neurosci, 2003, 23(34):10884–10891
5. Xia J, Chen X, Song C, et al. Postsynaptic excitation of prefrontal cortical pyramidal neurons by hypocretin-1/orexin A through the inhibition of potassium currents. J Neurosci Res, 2005, 82:729-736
6. Cathala L., Paupardin-Tritsch D. Neurotensin inhibition of the yperpolarization- activated cation current (Ih) in the rat substantia nigrapars compacta implicates the protein kinase C pathway. J Physiol (Lond), 1997, 503:87–97
7. LiuZ,BunneyEB, Appel SB, Brodie MS.Serotonin Reduces the Hyperpolarization- Activated Current (Ih) in VentralTegmental Area Dopamine Neurons: nvolvement of 5-HT2 Receptors and Protein Kinase C. J Neurophysio, 2003 90: 3201–3212
8. Brager DH, Johnston D. Plasticity of Intrinsic Excitability during Long-Term Depression Is Mediated through mGluR-Dependent Changes in Ih in Hippocampal CA1 Pyramidal Neurons. J Neurosci, 2007, 27:13926–13937.
9. Robinson RB, Siegelbaum SA. HYPERPOLARIZATION-ACTIVATED CATION CURRENTS: From Molecules to Physiological Function. Annu Rev Physiol, 2003, 65:453–480
10. Carr DB, Andrews GD, Glen WB, et al.α2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584: 437–450
11. Day M, Carr DB, Ulrich S, et al. Dendritic excitability of mouse frontal cortexpyramidal neurons is shaped by the interaction among HCN, Kir2, and Kleak channels. J Neurosci, 2005, 25:8776-87
12. Franz O, Liss B, Neu A, et al. Single-cell mRNA expression of HCN1 correlates with a fast gating phenotype of hyperpolarizationactivated cyclic nucleotide-gated ion channels (Ih) in central neurons. Eur J Neurosci, 2000, 12: 2685–2693
13. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 2001, 30 :345–354
14. Biel M. Cyclic Nucleotide-regulated Cation Channels. J Biol Chem, 2009, 284(14):9017-21
15. Shah BH and Catt KJ. GPCR-mediated transactivation of RTKs in the CNS: mechanisms and consequences. Trends Neurosci, 2004, 27, 48–53
16. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 1999, 98: 437–451
17. Hara J, Beuckmann CT, Nambu T, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 2001, 30 :345–354
18. Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat. Med, 2001, 6:991–997
19. Hofle N, Paus T, Reutens D, et al. Regional cerebral blood flow changes as a function of delta and spindle activity during slow wave sleep in humans. J Neurosci, 1997, 17:4800–4808
20. Paus T, Koski L, Caramanos Z, Westbury C. Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex: a review of 107 PET activation studies. Neuroreport, 1998, 9:R37–47
21. Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res, 2000, 9:335–352
22. Lambe EK, Aghajanian GK. Hypocretin (orexin) induces calcium transients in single spines postsynaptic to identified thalamocortical boutons in prefrontal slice. Neuron, 2003, 40:139–150.
23. Naumann, A., Bierbrauer, J., Przuntek, H., et al. Attentive and preattentive processingin narcolepsy as revealed by event related potentials (ERPs). Neuroreport, 2001, 12, 2807–2811
24. Rieger, M., Mayer, G., and Gauggel, S. Attention deficits in patients with narcolepsy. Sleep, 2003, 26, 36–43
25. Mishima K, Fujiki N, Yoshida Y, et al. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. Sleep, 2008, 31:1119-1126
26. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 1998, 92:573–585
27. Arnsten AF. Catecholamine and Second Messenger Influences on Prefrontal Cortical Networks of‘‘Representational Knowledge’’: A Rational Bridge between Genetics and the Symptoms of Mental Illness. Cerebral Cortex, 2007, 17 (supplement):i6--i15
28. Wang M, Ramos BP, Paspalas CD, et al.α2A-Adrenoceptors strengthen working memory networks by inhibiting cAMP HCN channel signaling in prefrontal cortex. Cell, 2007, 129:397–410
29. Hoang QV, Bajic D, Yanagisawa M, et al. Orexin (hypocretin) effects on GIRK channels. J Neurophysiol, 2003, 90(2): 693-702
30. Taheri S, Zeitzer JM, Mignot E. The role of hyocretins (orexins) in sleep regulation and narcolepsy. Annu Rev Neurosci, 2002;25:283-313
31. Foote SL, Aston-Jones G, Bloom FE. Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc Natl Acad Sci USA, 1980, 77: 3033—3037
32. Chen XW, Mu Y, Huang HP, et al. Hypocretin-1 potentiates NMDA receptor-mediated somatodendritic secretion from locus coeruleus neurons. J. Neurosci., 2008, 28:3202-08
33. Tanabe M. Inhibition of hyperpolarization-activated cation currents by phencyclidine and some sigma ligands in rat hippocampal CA1 pyramidal neurons in vitro. Neuropharmacology, 2007, 53: 406-414.
34. Nishino S. The hypothalamic peptidergic system, hypocretin/orexin and vigilance control. Neuropeptides, 2007, 41:117-133
1. Noma A, Irisawa H. Membrane currents in the rabbit sinoatrial node cell a studied by the double microelectrode method. Pfl¨ugers Arch., 1976, 364:45–52
2. Brown HF, DiFrancesco D, Noble SJ. How does adrenaline accelerate the heart? Nature, 1979, 280:235–36
3. Halliwell JV, Adams PR. Voltageclamp analysis of muscarinic excitation in hippocampal neurons. Brain Res, 1982, 250:71–92
4. Chen S, Wang J, Siegelbaum SA. Properties of hyperpolarization-activated pacemaker current defined by coassembly of hcn1 and hcn2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol., 2001, 117:491–504
5. Wainger BJ, DeGennaro M, Santoro B, et al. Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature, 2001, 411:805–10
6. Wahl-Schott C, Biel M. HCN channels: structure, cellular regulation and physiological function. Cell Mol Life Sci, 2009, 66(3):470-94
7. Santoro B, Tibbs GR.The HCN gene family: molecular basis of the hyperpolar ization-activated pacemaker channels. Ann. NY Acad. Sci., 1999, 868:741–64
8. Ulens, C. and Tytgat, J. Functional heteromerization of HCN1 and HCN2 pacemaker channels. J. Biol. Chem, 2001, 276, 6069–6072
9. Xue, T., Marban, E. and Li, R. A. Dominant-negative suppression of HCN1- and HCN2-encoded pacemaker currents by an engineered HCN1 construct: insights into structure-function relationships and multimerization. Circ. Res. 2002, 90, 1267–1273
10. Altomare, C., Terragni, B., Brioschi, C., et al. Heteromeric HCN1-HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node. J. Physiol, 2003, 549, 347–359
11. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol., 1993, 55:455–72
12. Raman IM, Bean BP. Ionic currents underlying spontaneous action potentials in isolated cerebellar Purkinje neurons. J. Neurosci., 1999,19:1663–74
13. Thoby-Brisson M, Telgkamp P, Ramirez JM. The role of the hyperpolarization- activated current in modulating rhythmic activity in the isolated respiratory network ofmice. J. Neurosci., 2000, 20:2994–3005
14. Irisawa H, Brown HF, GilesW. Cardiac pacemaking in the sinoatrial node. Physiol. Rev, 1993, 73:197–227
15. Noma A, Morad M, Irisawa H. Does the“pacemaker current”generate the diastoli c depolarization in the rabbit SA node cells? Pfl¨ugers Arch., 1983, 397:190–94
16. Vassalle M. Cardiovascular controversies: The pacemaker current, if, does not play an important role in regulating SA node pacemaker activity. Cardiovasc., Res. 1995, 30:309–10
17. Robinson R B, Siegelbaum S A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu Rev Physiol, 2003, 65:453-480
18. Kaupp, U. B. and Seifert, R. Cyclic nucleotide-gated ion channels. Physiol. Rev, 2002, 82, 769–824
19. Craven, K. B. and Zagotta, W. N. CNG and HCN channels: two peas, one pod. Annu. Rev. Physiol., 2006,68, 375–401
20. Biel, M. and Michalakis, S. Function and dysfunction of CNG channels: insights from channelopathies and mouse models. Mol. Neurobiol., 2007, 35, 266–277
21. Luthi A, McCormick DA. Hcurrent: properties of a neuronal and network pacemaker. Neuron, 1998, 21:9–12
22. Bal T, McCormick DA.Synchronized oscillations in the inferior olive are control- led by the hyperpolarizationactivated cation current I(h). J. Neurophysiol., 1997, 77:3145–56
23. Maccaferri G, McBain CJ. The hyperpolarization-activated current (Ih) and its contribution to pacemaker activity in rat CA1 hippocampal stratum oriensalveus interneurones. J. Physiol., 1996, 497(Pt.1):119–30
24. Gasparini S, DiFrancesco D. Action of the hyperpolarization-activated current (Ih) blocker ZD 7288 in hippocampal CA1 neurons. Pfl¨ugers Arch, 1997, 435:99–10
25. Shin KS, Rothberg BS, Yellen G.. Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate. J. Gen. Physiol, 2001, 117:91–101
26. DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature, 1991, 351:145–47
27. Ludwig A, Zong X, Jeglitsch M, Hofmann F, Biel M. A family of hyperpolar ization-activated mammalian cation channels. Nature, 1998, 393:587–91
28. Wang M, Ramos BP, Paspalas CD, et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell, 2007; 129(2): 397-410
29. Bickmeyer U, Heine M, et al . Differential modulation of Ih by 5-HT receptors in mouse CA1 hippocampal neurons.Euro J Neurosci, 2002, (16):209-218
30. Vargas G, Lucero MT. Dopamine modulates inwardly rectifying Hyperpolar ization -activated current (Ih) in cultured rat olfactory receptor neurons. J Neurophysiol, 1999, 81(1): 149-158
31. Santoro, B., Grant, S.G., Bartsch,D.et al. Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proc. Natl. Acad. Sci. USA, 1997, 94,14815–14820
32. Santoro, B., Chen, S., Luthi, A., et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J. Neurosci, 2000,20, 5264–5275
33. Moosmang, S., Biel, M., Hofmann, F. et al. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol. Chem, 1999, 380, 975–980
34. Notomi, T. and Shigemoto, R. Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain. J. Comp. Neurol, 2004, 471, 241–276
35. MannikkoR, Elinder F, LarssonHP. Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages. Nature, 2002, 419:837–41
36. Rothberg BS, Shin KS, Phale PS, et al.Voltage-controlled gating at the intrace- llular entrance to a hyperpolarization-activated cation channel. J. Gen. Physiol, 2002, 119:83–91
37. Sanguinetti MC, Xu QP.Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes. J. Physiol,1999, 514 (Pt. 3): 667–75
38. Chen J, Mitcheson JS, Tristani-Firouzi M, et al.The S4-S5 linker couples voltage sensing and activation of pacemaker channels. Proc. Natl. Acad. Sci. USA, 2001,98:11277–82
39. Golgi, C. (1989) On the structure of nerve cells. 1898. J. Microsc. 155, 3–7
40. Ramon y Cajal, S. (1911) Histologie du systeme nerveux de l’homme et des vertebres. Maloine
41. Migliore, M. and Shepherd, G.M. Emerging rules for the distribution of active dendritic conductances. Nat. Rev. Neurosci, 2002, 3, 362–370
42. Williams, S.R. and Stuart, G.J. Role of dendritic synapse location in the control of action potential output. Trends Neurosci, 2003, 26, 147–154
43. Magee, J.C. and Johnston, D. Plasticity of dendritic function. Curr. Opin. Neurobiol, 2005,15, 334–342
44. Lai, H.C. and Jan, L.Y. The distribution and targeting of neuronal voltage-gated ion channels. Nat. Rev. Neurosci, 2006, 7, 548–562
45. Spruston, N. Pyramidal neurons: dendritic structure and synaptic integration. Nat. Rev. Neurosci, 2008, 9, 206–221
46. Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci, 1998, 18: 7613– 7624
47. Lorincz, A., Notomi, T., Tamas, G., et al Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat. Neurosci , 2002, 5: 1185–1193
48. Berger T, Larkum ME, Luscher H-R. High Ih channel density in the distal apical dendrite of layer V pyramidal cells increases bidirectional attenuation of EPSPs. J Neurophysiol, 2001, 85, 855–868
49. Lujan, R., Albasanz, J.L., Shigemoto, R. et al. Preferential localization of the hyperpolarization-activated cyclic nucleotide-gated cation channel subunit HCN1 in basket cell terminals of the rat cerebellum. Eur J Neurosci ,2005,21, 2073-2082
50. Aponte, Y., Lien, C., Reisinger, E. and Jonas, P. Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus. J Physiol, 2006, 574, 229-243
51. Brewster, A.L., Chen, Y., Bender, R.A., et al. Quantitative analysis and subcellular distribution of mRNA and protein expression of the hyperpolarization-activated cyclic nucleotide-gated channels throughout development in rat hippocampus. Cereb Cortex, 2007, 17, 702-712
52. Cuttle, M.F., Rusznak, Z., Wong, A.Y., Owens, S. and Forsythe, I.D. Modulation of a presynaptic hyperpolarization-activated cationic current (I(h)) at an excitatory synaptic terminal in the rat auditory brainstem. J Physiol, 2001, 534, 733-744
53. Soleng, A.F., Chiu, K. and Raastad, M. Unmyelinated axons in the rat hippocam- pus hyperpolarize and activate an H current when spike frequency exceeds 1 Hz. J Physiol, 2003, 552, 459-470
54. Bender, R.A., Kirschstein, T., Kretz, O., et al. () Localization of HCN1 channels to presynaptic compartments: novel plasticity that may contribute to hippocampal maturation. J Neurosci, 2007, 27, 4697-4706
55. Nicoll A, Larkman A, Blakemore C. Modulation of EPSP shape and efficacy by intrinsic membrane conductances in rat neocortical pyramidal neurons in vitro. J. Physiol, 1993, 468:693–710
56. Magee JC. Dendritic lh normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci, 1999, 2:508–14
57. Williams SR, Stuart GJ. Site independence of EPSP time course is mediated by dendritic I(h) in neocortical pyramidal neurons. J. Neurophysiol, 2000,83:3177–82
58. Fernandez N, Andreasen M, Nedergaard S. Influence of the hyperpolarization- activated cation current, I(h), on the electrotonic properties of the distal apical dendrites of hippocampal CA1 pyramidal neurones. Brain Res, 2002, 930:42–52
59. Poolos NP, Migliore M, Johnston D. 2002. Pharmacological upregulation of hchannels reduces the excitability of pyramidal neuron dendrites. Nat. Neurosci. 5:767–74
60. Buzsaki G.. Theta oscillations in the hippocampus. Neuron, 2002, 33:325–40
61. Staubli U, Lynch G.. Stable hippocampal long-term potentiation elicited by‘theta’pattern stimulation. Brain Res, 1987, 435:227–34
62. Leung LS,YuHW. Theta-frequency resonance in hippocampal CA1 neurons in vitro demonstrated by sinusoidal current injection. J. Neurophysiol, 1998, 79: 1592–96
63. Pike FG, Goddard RS, Suckling JM, et al. Distinct frequency preferences of different types of rat hippocampal neurones in response to oscillatory input currents. J. Physiol, 2000, 529(Pt. 1):205–13
64. Ulrich D. Dendritic resonance in rat neocortical pyramidal cells. J. Neurophysiol, 2002, 87:2753–59
65. Arnsten, A. F. Catecholamine and second messenger influences on prefrontal cortical networks of”representational knowledge”: a rational bridge between genetics and the symptoms ofmental illness.Cereb.Cortex, 2007, 17, i6–15
66. Vijayraghavan, S.,Wang, M., Birnbaum, et al.Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat. Neurosci, 2007, 10, 376–384
67. Williams, G. V. and Goldman-Rakic, P. S. Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature, 1995, 376, 572–575
68. Arnsten, A. F. Through the looking glass: differential noradenergic modulation of prefrontal cortical function. Neural. Plast, 2000, 7, 133–146
69. Carr DB, Andrews GD, Glen WB, et al.α2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584: 437–450