Hua Hu

1.    Hu H‡, Roth FC, Vandael D, Jonas P‡ (2018) Complementary Tuning of Na+ and K+ Channel Gating Underlies Fast and Energy-Efficient Action Potentials in GABAergic Interneuron Axons. Neuron, 98:156-165.
2.    Hu H, Gan J, Jonas P (2014) Fast-spiking, parvalbumin+ GABAergic interneurons: from cellular design to microcircuit function. Science 345: 1255263.                
3.    Hu H and Jonas P (2014) A supercritical density of Na+ channels ensures fast signaling in GABAergic interneuron axons. Nature Neuroscience 17: 686-693.         
4.    Kim S, Guzman SJ, Hu H, Jonas P (2012) Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons. Nature Neuroscience 15: 600-606.           
5.    Hu H, Martina M and Jonas P (2010) Dendritic mechanisms underlying rapid synaptic activation of fast-spiking hippocampal interneurons. Science 327: 52-58.     
6.    Vervaeke K, Hu H, Graham LJ and Storm JF (2006) Contrasting effects of the persistent Na+ current on neuronal excitability and spike timing. Neuron 49: 257-270.
7.    Peters HC, Hu H, Pongs O, Storm JF, and Isbrandt D (2005) Conditional transgenic suppression of M-channels in mouse brain reveals functions in neuronal excitability, resonance, and behavior. Nature Neuroscience 8: 51-60.

• Kriener, Birgit; Hu, Hua & Vervaeke, Koen Gerard Alois (2022). Parvalbumin interneuron dendrites enhance gamma oscillations. Cell reports. 39(11). doi: 10.1016/j.celrep.2022.110948. Fulltekst i vitenarkiv Vis sammendrag

  Dendrites are essential determinants of the input-output relationship of single neurons, but their role in network computations is not well understood. Here, we use a combination of dendritic patch-clamp recordings and in silico modeling to determine how dendrites of parvalbumin (PV)-expressing basket cells contribute to network oscillations in the gamma frequency band. Simultaneous soma-dendrite recordings from PV basket cells in the dentate gyrus reveal that the slope, or gain, of the dendritic input-output relationship is exceptionally low, thereby reducing the cell’s sensitivity to changes in its input. By simulating gamma oscillations in detailed network models, we demonstrate that the low gain is key to increase spike synchrony in PV basket cell assemblies when cells are driven by spatially and temporally heterogeneous synaptic inputs. These results highlight the role of inhibitory neuron dendrites in synchronized network oscillations.

• Kriener, Birgit; Hu, Hua & Vervaeke, Koen Gerard Alois (2021). Parvalbumin interneuron dendrites enhance gamma oscillations. BioRxiv. ISSN 0362-4331. doi: 10.1101/2021.06.22.449483. Fulltekst i vitenarkiv
• Roth, Fabian Christoph & Hu, Hua (2020). An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons. Nature Communications. doi: 10.1038/s41467-020-15791-y. Fulltekst i vitenarkiv Vis sammendrag

  During high-frequency network activities, fast-spiking, parvalbumin-expressing basket cells (PV+-BCs) generate barrages of fast synaptic inhibition to control the probability and precise timing of action potential (AP) initiation in principal neurons. Here we describe a subcellular specialization that contributes to the high speed of synaptic inhibition mediated by PV+-BCs. Mapping of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel distribution in rat hippocampal PV+-BCs with subcellular patch-clamp methods revealed that functional HCN channels are exclusively expressed in axons and completely absent from somata and dendrites. HCN channels not only enhance AP initiation during sustained high-frequency firing but also speed up the propagation of AP trains in PV+-BC axons by dynamically opposing the hyperpolarization produced by Na+-K+ ATPases. Since axonal AP signaling determines the timing of synaptic communication, the axon-specific expression of HCN channels represents a specialization for PV+-BCs to operate at high speed.

• Hu, Hua; Roth, Fabian Christoph; Vandael, David & Jonas, Peter (2018). Complementary Tuning of Na+ and K+ Channel Gating Underlies Fast and Energy-Efficient Action Potentials in GABAergic Interneuron Axons. Neuron. ISSN 0896-6273. 98(1), s. 156–165.e6. doi: 10.1016/j.neuron.2018.02.024. Fulltekst i vitenarkiv Vis sammendrag

  Fast-spiking, parvalbumin-expressing GABAergic interneurons (PV+-BCs) express a complex machinery of rapid signaling mechanisms, including specialized voltage-gated ion channels to generate brief action potentials (APs). However, short APs are associated with overlapping Na+ and K+ fluxes and are therefore energetically expensive. How the potentially vicious combination of high AP frequency and inefficient spike generation can be reconciled with limited energy supply is presently unclear. To address this question, we performed direct recordings from the PV+-BC axon, the subcellular structure where active conductances for AP initiation and propagation are located. Surprisingly, the energy required for the AP was, on average, only ∼1.6 times the theoretical minimum. High energy efficiency emerged from the combination of fast inactivation of Na+ channels and delayed activation of Kv3-type K+ channels, which minimized ion flux overlap during APs. Thus, the complementary tuning of axonal Na+ and K+ channel gating optimizes both fast signaling properties and metabolic efficiency.

• Hu, Hua & Vervaeke, Koen Gerard Alois (2017). Synaptic integration in cortical inhibitory neuron dendrites. Neuroscience. ISSN 0306-4522. 368, s. 115–131. doi: 10.1016/j.neuroscience.2017.06.065. Fulltekst i vitenarkiv
• Hu, Hua; Gan, Jian & Jonas, Peter (2014). Interneurons. Fast-spiking, parvalbumin⁺ GABAergic interneurons: from cellular design to microcircuit function. Science. ISSN 0036-8075. 345, s. 1255263–1255263. doi: 10.1126/science.1255263. Fulltekst i vitenarkiv
• Hu, Hua & Jonas, Peter (2014). A supercritical density of Na+ channels ensures fast signaling in GABAergic interneuron axons. Nature Neuroscience. ISSN 1097-6256. 17, s. 686–693. doi: 10.1038/nn.3678. Fulltekst i vitenarkiv
• Kim, Sooyun; Guzman, Segundo J; Hu, Hua & Jonas, Peter (2012). Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons. Nature Neuroscience. ISSN 1097-6256. 15, s. 600–606. doi: 10.1038/nn.3060. Fulltekst i vitenarkiv
• Nörenberg, A; Hu, Hua; Vida, Imre; Bartos, Marlene & Jonas, Peter (2010). Distinct nonuniform cable properties optimize rapid and efficient activation of fast-spiking GABAergic interneurons. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 107(2), s. 894–899. doi: 10.1073/pnas.0910716107. Fulltekst i vitenarkiv
• Hu, Hua; Martina, Marco & Jonas, Peter (2010). Dendritic Mechanisms Underlying Rapid Synaptic Activation of Fast-Spiking Hippocampal Interneurons. Science. ISSN 0036-8075. 327(5961), s. 52–58. doi: 10.1126/science.1177876. Fulltekst i vitenarkiv
• Storm, Johan Frederik; Vervaeke, Koen Gerard Alois; Hu, Hua & Graham, LJ (2009). Functions of the persistent Na+ current in cortical neurons revealed by dynamic clamp. I Destexhe, Alain & Bal, Thierry (Red.), Dynamic-clamp: From Principles To Applications. Springer. ISSN 9780387892788. s. 1–33. Fulltekst i vitenarkiv
• Storm, Johan Frederik; Vervaeke, Koen Gerard Alois & Hu, Hua (2009). Functions of the Persistent Na+ Current in Cortical Neurons Revealed by Dynamic Clamp. I Destexhe, Alain & Bal, Thierry (Red.), Dynamic-clamp: From Principles To Applications. Springer. ISSN 9780387892788. s. 165–199. Fulltekst i vitenarkiv
• Hu, Hua; Vervaeke, Koen; Graham, Lyle & Storm, Johan Frederik (2009). Complementary Theta Resonance Filtering by Two Spatially Segregated Mechanisms in CA1 Hippocampal Pyramidal Neurons. Journal of Neuroscience. ISSN 0270-6474. 29(46), s. 14472–14483. doi: 10.1523/JNEUROSCI.0187-09.2009. Fulltekst i vitenarkiv
• Gu, Ning; Hu, Hua; Vervaeke, Koen Gerard Alois & Storm, Johan Frederik (2008). SK (K(Ca)2) Channels Do Not Control Somatic Excitability in CA1 Pyramidal Neurons But Can Be Activated by Dendritic Excitatory Synapses and Regulate Their Impact. Journal of Neurophysiology. ISSN 0022-3077. 100(5), s. 2589–2604. doi: 10.1152/jn.90433.2008. Fulltekst i vitenarkiv
• Hu, Hua; Vervaeke, Koen Gerard Alois & Storm, Johan Frederik (2007). M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region. Journal of Neuroscience. ISSN 0270-6474. 27, s. 1853–1867. doi: 10.1523/JNEUROSCI.4463-06.2007. Fulltekst i vitenarkiv
• Vervaeke, Koen Gerard Alois; Hu, Hua; Graham, LJ & Storm, Johan Fredrik (2006). Contrasting effects of the persistent Na+ current on neuronal excitability and spike timing. Neuron. ISSN 0896-6273. 49, s. 257–270. Fulltekst i vitenarkiv
• Vervaeke, Koen Gerard Alois; Gu, Ning; Agdestein, Christine; Hu, Hua & Storm, Johan Frederik (2006). Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. Journal of Physiology. ISSN 0022-3751. 576, s. 235–256. Fulltekst i vitenarkiv
• Lancaster, B; Hu, Hua; Gibb, B & Storm, Johan Frederik (2006). Kinetics of ion channel modulation by cAMP in rat hippocampal neurones. Journal of Physiology. ISSN 0022-3751. 576, s. 403–416. Fulltekst i vitenarkiv
• Peters, Christian; Hu, Hua; Pongs, Olaf; Storm, Johan Frederik & Isbrandt, Dirk (2005). Conditional transgenic suppression of M channels in mouse brain reveals functions in neuronal excitability, resonance and behavior. Nature Neuroscience. ISSN 1097-6256. 8(1), s. 51–60. doi: 10.1038/nn1375. Fulltekst i vitenarkiv
• Gu, Ning; Vervaeke, Koen Gerard Alois; Hu, Hua & Storm, Johan Frederik (2005). Kv7/KCNQ/M and HCN/h, but not K(Ca)2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells. Journal of Physiology. ISSN 0022-3751. 566, s. 689–715. Fulltekst i vitenarkiv
• Sausbier, M; Hu, Hua; Arntz, C; Feil, S; Kamm, S & Adelsberger, H [Vis alle 17 forfattere av denne artikkelen] (2004). Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 101(25), s. 9474–9478. Fulltekst i vitenarkiv
• Hu, Hua; Vervaeke, Koen Gerard Alois & Storm, Johan Fredrik (2002). Two forms of electrical resonance at theta frequencies, generated by M-current, h-current and persistent Na+ current in rat hippocampal pyramidal cells. Journal of Physiology. ISSN 0022-3751. 545(3), s. 783–805. Fulltekst i vitenarkiv
• Sailer, Claudia A.; Hu, Hua; Kaufmann, Walter; Trieb, Maria; Schwarzer, Christoph & Storm, Johan Fredrik [Vis alle 7 forfattere av denne artikkelen] (2002). Regional differences in distribution and functional expression of small-conductance Ca2+ activated K+ channels in rat brain. Journal of Neuroscience. ISSN 0270-6474. s. 9698–9707. Fulltekst i vitenarkiv
• Lancaster, B.; Hu, Hua; Ramakers, G. M. J. & Storm, Johan Fredrik (2001). Interaction between synaptic excitation and slow afterhyperpolarization current in rat hippocampal pyramidal cells. Journal of Physiology. ISSN 0022-3751. 536,3, s. 809–823. Fulltekst i vitenarkiv
• Hu, Hua; Shao, Li-Rong; Chavoshy, Sorush; Gu, Ning; Trieb, Maria & Behrens, Ralf [Vis alle 11 forfattere av denne artikkelen] (2001). Presynaptic Ca2+-Activated K+ Channels in Glutamatergic Hippocampal Terminals and Their Role in Spike Repolarization and Regulation of Transmitter Release. Journal of Neuroscience. ISSN 0270-6474. 21, s. 1–13. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Storm, Johan Frederik; Vervaeke, Koen Gerard Alois; Hu, Hua & Graham, LJ (2009). Dynamic clamp. Springer. ISBN 9780387892788. 429 s. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Glovaci, Iulia; Vervaeke, Koen Gerard Alois & Hu, Hua (2023). Cholecystokinin-expressing interneurons as intermediaries of noradrenergic suppression of hippocampal granule cells. Fulltekst i vitenarkiv
• Bojarskaite, Laura; Enger, Rune; Hu, Hua & Boccara, Charlotte (2020). Hvorfor sover vi? Fulltekst i vitenarkiv
• Boccara, Charlotte N; Hu, Hua; Enger, Rune & Bojarskaite, Laura (2020). Hvorfor sover vi? Fulltekst i vitenarkiv
• Vervaeke, Koen Gerard Alois; Hu, Hua & Kriener, Birgit (2019). Dendritic properties of parvalbumin interneurons enhance robustness of gamma oscillations. Fulltekst i vitenarkiv
• Kriener, Birgit; Hu, Hua & Vervaeke, Koen Gerard Alois (2018). Stabilization of gamma oscillations in basket cell networks: the role of dendritic attenuation. Fulltekst i vitenarkiv
• Roth, Fabian Christoph; Storm, Johan Frederik & Hu, Hua (2018). A unique subcellular distribution of HCN channels accelerates action potential propagation in GABAergic interneuron axons. Fulltekst i vitenarkiv
• Hu, Hua (2018). HCN channels in hippocampal inhibitory interneurons: from subcellular distribution to functions. Fulltekst i vitenarkiv Vis sammendrag

  The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are cation-permeable channels that are opened by membrane potential hyperpolarization. The HCN channels play a key role in a broad array of important physiological functions in the body, ranging from contributing to the spontaneous rhythmic activity in the heart to influencing the resting membrane potential of neurons in the nervous system. The HCN channels are widely expressed in the brain. In the cortex, these channels are enriched in glutamatergic pyramidal neuron dendrites, and they represent an important determinant of the integrative property of pyramidal neurons. The HCN channels are also expressed in -aminobutyric acid (GABA)–releasing (GABAergic) interneurons. In contrast to the wealth of knowledge gained from pyramidal neurons, the subcellular distribution and function of HCN channels in inhibitory interneurons are less well-understood. To address this issue, my group has performed subcellular patch-clamp recordings from axons and dendrites of hippocampal parvalbumin-expressing interneurons that produce fast feedforward and feedback inhibition. Our result has revealed a unique HCN channel spatial gradient in parvalbumin-expressing interneurons, with the HCN channels being confined to the interneuron axon. This cell type-specific subcellular distribution of HCN channels make a major contribution to the fast and reliable action potential propagation in parvalbumin-expressing interneuron axons.

• Kriener, Birgit; Hu, Hua & Vervaeke, Koen Gerard Alois (2018). Dendritic properties of parvalbumin interneurons enhance robustness of gamma oscillations. Fulltekst i vitenarkiv
• Nilsen, Andre Sevenius; Arena, Alessandro; Juel, Bjørn Erik; Storm, Johan Frederik; Murphy, Ricardo & Hu, Hua [Vis alle 7 forfattere av denne artikkelen] (2017). Forsknigstorget: Hvordan kan hjernen skape bevissthet. Fulltekst i vitenarkiv
• Hu, Hua & Jonas, Peter (2016). Energy efficient action potential signaling in GABAergic inhibitory axons. Fulltekst i vitenarkiv
• Jonas, Peter & Hu, Hua (2016). Energy-efficient action potential signaling in inhibitory interneuron axons. Fulltekst i vitenarkiv
• Hu, Hua; Vervaeke, Koen Gerard Alois & Storm, Johan Frederik (2007). Theta resonance regulates frequency-dependence of postsynaptic responses and signal transfer along the apical dendrites of hippocampal pyramidal cells. Fulltekst i vitenarkiv
• Vervaeke, Koen Gerard Alois; Hu, Hua; Graham, LJ & Storm, Johan Frederik (2005). Persistent sodium current modulates temporal precision of action potential discharge in CA1 pyramidal cells. Fulltekst i vitenarkiv Vis sammendrag

  The temporal precision with which synaptic input initiates action potentials is likely to be important for neuronal information coding. By combining whole cell recording/dynamic clamp experiments and computer modeling, we studied the contribution of the persistent Na+ current (INaP) to the temporal precision of excitatory postsynaptic potential (EPSP)-triggered action potentials in CA1 pyramidal neurons. Stimulation with an electrode placed in str. radiatum evoked EPSPs in CA1 pyramidal neurons. The stimulus strength was carefully adjusted, so that only ~ 45% of the EPSPs triggered an action potential, under each experimental condition. In the control condition, CA1 pyramidal neurons showed high variability in their EPSP-triggered spike timing (Var = 111.2+/-40.1 ms, n=8). When we cancelled the cell's intrinsic INaP with dynamic clamp, the temporal precision of discharge significantly increased (Var = 2.6+/-0.4 ms, n=8, p=0.03). Also, the rise and decay of subthreshold EPSPs were significantly accelerated when INaP was cancelled (n=8, p<0.05). Similar results were obtained with a computational model of a CA1 pyramidal cell. In conclusion, our results indicate that INaP strongly modulates subthreshold EPSP time course and temporal precision of spike discharge in CA1 pyramidal neurons.

• Storm, Johan Frederik; Vervaeke, Koen Gerard Alois; Gu, Ning & Hu, Hua (2005). NMDA receptor - activated postsynaptic SK ( KCa2 ) K+ channels can regulate postsynaptic excitatory responses but do not underlie somatic spike afterhyperpolarizations or adaptation in rat CA1 pyramidal neurons. Fulltekst i vitenarkiv Vis sammendrag

  Small-conductance, apamin-sensitive (SK) Ca-dependent K-channels have been proposed to control somatic excitability by producing afterhyperpolarizations (mAHP, sAHP) and adaptation in hippocampal pyramidal neurons. SK1-3 subunits show high expression in hippocampus, and voltage-clamp data show a robust SK current in CA1 and CA3 pyramidal cells. However, data from our lab have consistently indicated that the somatic mAHP following a spike train and the associated spike adaptation is due to M-channels (Kv7/KCNQ) rather than SK channels (Storm, J. Physiol. 1989; Gu et al. J.Physiol. 2005, in press). Furthermore, sAHP and SK channels have been shown to differ pharmacologically. We and others have therefore proposed that the SK channels in these cells must have other functions than producing somatic AHPs and adaptation, most likely in dendritic compartments (Cai &al Neuron 44:351-64; Gu &al 2005). We tested these ideas by field potential and intracellular recordings from CA1 pyramidal neurons in mouse and rat hippocampal slices. Stimulation of str.radiatum axons (5-10 stim.at 100 Hz) produced a train of field synaptic potentials (fEPSPs) and spikes. Apamin (100 nM) reduced the amplitude of the last spikes in the train (n=6) - an effect that was prevented or reversed by the NMDA-receptor blocker APV (100 uM). Pure NMDA-R fEPSPs evoked in low Mg medium with DNQX (100 uM) were enhanced after apamin application in 2 of 10 slices tested. However, apamin had no effect on the somatic mAHP or sAHP. Presumably postsynaptic SK-channels triggered by NMDA-R activation produce a re-/hyperpolarization that promote deinactivation of Na+ channels, thus facilitating late spikes in the train, whereas the NMDA-R-dependent depolarization has the opposite effect. These results suggest that postsynaptic SK channels in CA1 pyramidal cells are triggered by NMDA-R and can regulate synaptic efficacy and integration.

• Storm, Johan; Hu, Hua; Vervaeke, Koen Gerard Alois & Gu, Ning (2005). Threshold currents in hippocampal neurons. Fulltekst i vitenarkiv
• Ruth, P; Hu, Hua; Sausbier, M; Arntz, C; Feil, S & Kamm, S [Vis alle 17 forfattere av denne artikkelen] (2004). Cerebellar ataxia and Purkinje cell dysfunction caused by CA - activated K - channel deficiency. Fulltekst i vitenarkiv Vis sammendrag

  Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the BK channels - a unique calcium- and voltage-activated potassium channel type - has remained elusive. Here we report that mice lacking BK channels (BK-/-) show cerebellar dysfunction in the form of abnormal conditioned eye blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK-/- mice showed a dramatic reduction in spontaneous activity of the BK-/- cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels, were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a novel animal model of cerebellar ataxia.

• Gu, Ning; Hu, Hua; Sausbier, M; Arntz, C; Ruth, P & Storm, Johan Frederik (2004). Pre - and postsynaptic functions of BK - type potassium channels in hippocampal CA1 pyramidal cells studied by knockout of the gene encoding the pore - forming channel subunit in mice. Fulltekst i vitenarkiv
• Hu, Hua; Gu, Ning & Storm, Johan Frederik (2004). Apamin - sensitive SK potassium channels underlie medium - duration afterhyperpolarizations ( mAHP ) in rat subicular pyramidal neurons but not in CA1 pyramidal neurons. Fulltekst i vitenarkiv
• Gu, Ning; Hu, Hua; Vervaeke, Koen Gerard Alois & Storm, Johan Frederik (2004). M- and H-channels, but not SK channels, generate the medium afterhyperpolarisation (mAHP) following single spikes and spike bursts in CA1 pyramidal cells. Fulltekst i vitenarkiv
• Vervaeke, Koen Gerard Alois; Hu, Hua & Storm, Johan Frederik (2004). An "inhibitory" action of voltage-dependent persistent sodium channels: amplification of the medium and slow afterhyperpolarisations in CA1 hippocampal pyramidal neurons. Fulltekst i vitenarkiv Vis sammendrag

  In CA1 pyramidal neurons, a train of action potentials shows adaptation of the firing frequency and is followed by afterhyperpolarizations of medium (mAHP) and subsequent slow (sAHP) duration. Both AHPs and the adaptation reflect the activation of voltage- and calcium-dependent potassium currents. By hyperpolarizing the membrane potential, these currents create a refractory period making the cell less likely to spike. Here we report a substantial amplification of the AHPs by the persistent sodium current, creating a paradoxal inhibitory effect as sodium currents are usually referred to as being �excitatory�. We used a CA1 pyramidal cell model that reproduces accurately the spike-shape, spike adaptation and both AHPs. The model contains several currents and describes calcium buffering and diffusion through intracellular subcompartments. In addition, we performed whole cell recordings in hippocampal brain slices to test the theoretical predictions. We simulated trains of action potentials by various protocols. At depolarized potentials, we found that the persistent sodium current amplifies the peak amplitude of both the mAHP and sAHP by 20-30 percent. The amplification of the AHPs is voltage-dependent and increases with increased depolarization of the membrane potential. Furthermore, omitting the persistent sodium current causes a slight decrease in spike frequency throughout the spike train. When the persistent sodium current is omitted in the model, the decrease of the AHP amplitudes is neither due to a decreased activation of the M-current or a reduced calcium influx. Experimentally we used whole-cell recordings from CA1 pyramidal cells in rat hippocampal slices. We injected current waveforms resembling the mAHP and sAHP and found effects quantitatively and qualitatively similar to the model predictions. Our results indicate that the persistent sodium current substantially amplifies the amplitudes of both mAHP and sAHP, thereby decreasing subsequent excitability.

• Gu, Ning; Hu, Hua; Ruth, Peter & Storm, Johan Fredrik (2004). Pre- and postsynaptic functions of BK-type potassium channels in hippocampal CA1 pyramidal cells studied by knockout of the gene encoding the pore-forming channel subunit in mice. Fulltekst i vitenarkiv
• Vervaeke, Koen Gerard Alois; Hu, Hua; Graham, Lyle & Storm, Johan Frederik (2004). The persistent sodium current enhances afterhyperpolarisations and reduces f/I gain in pyramidal neurons. Fulltekst i vitenarkiv
• Storm, Johan Frederik & Hu, Hua (2003). Theta - resonance generated by H - and M - channels in hippocampal Str.oriens interneurons. Fulltekst i vitenarkiv Vis sammendrag

  Theta oscillations are suggested to be important for hippocampus-dependent spatial navigation, learning and memory (Buzaki, Neuron 2002), and may result from an interplay between synaptic input and intrinsic resonance properties of hippocampal neurons. We recently showed that there are two forms of theta resonance of CA1 pyramidal cells: M-resonance generated (at depolarized potentials) primarily by the M current and H-resonance generated (at more negative potentials) by the H current (H. Hu et al., J.Physiol, 2002). We have now examined the resonance properties of CA1 str.oriens interneurons in rat hippocampal slices, by injecting oscillating currents with a linear increase in frequency (ZAP current). Whole cell recordings were obtained from Str.oriens interneurons, visualized by IR/DIC microscopy. The cells recorded were nonpyramidal, with a predominantly horizontal (i.e. parallel to str. pyramidale) orientation of their main dendrites. In response to ZAP current injection (0-30 Hz over 20-30 s) at -70 mV to -80 mV, more than 90% of the Str.oriens interneurons showed a clear H-resonance) that was readily blocked by the H-channel blocker ZD-7288 (10 uM). When tested at -50 to -60 mV, some of these interneurons also showed a clear M-resonance that was readily blocked by the M-channel blocker XE-991 (10 uM). We conclude that the Str.oriens interneurons, like the pyramidal cells in the CA1 area, can show two forms of theta resonance: H-resonance caused by H-channels and M-resonance that caused by M-channels. Considering the proposed importance of hippocampal inhibitory interneurons in generating theta oscillations (Buzaki, Neuron, 2002; Pike et al. J.Physiol. 2000), the intrinsic resonance properties of the Str.oriens interneurons are likely to play a significant role in hippocampal functions.

• Storm, Johan Frederik & Hu, Hua (2003). Transient BK channel current in hippocampal CA1 pyramidal neurons. Fulltekst i vitenarkiv Vis sammendrag

  Hippocampal CA1 pyramidal neurons show a pronounced frequency-dependent spike broadening that appears to be mainly mediated by a transient BK channel current (ICT: Shao et al., J.Physiol 1999). Here we present voltage-clamp data on ICT from whole-cell recording from CA1 pyramidal cells in rat hippocampal slices. Outward currents evoked by a train of 20ms depolarizing steps delivered at 30Hz in the presence of TTX. They contained a fast-inactivating and a sustained component. The fast-inactivating component, ICT, was abolished by Calcium-free medium or BK channel blockers (100 nM iberiotoxin, IbTX or 0.5-1 mM TEA), but was resistant to 4-AP. The IbTx-sensitive current, obtained by subtracting the outward current before and after IbTx application, showed a time constant of inactivation of 2.4ms, with half maximal (V1/2) steady state activation and inactivation of -27mV and -35mV, respectively. The time constant of recovery from inactivation of the IbTx-sensitive current, as studied with a paired pulse protocol with increasing inter-pulse intervals, was 86 ms. We conclude that hippocampal CA1 pyramidal neurons are equipped with a fast inactivating IbTx-sensitive BK current, ICT, which is likely to produce to the frequency dependent spike broadening in these cells.

• Gu, Ning; Hu, Hua; Vervaeke, Koen Gerard Alois & Storm, Johan Fredrik (2003). M- AND H-CHANNELS, BUT NOT SK CHANNELS, GENERATE THE MEDIUM AFTERHYPERPOLARIZATION (mAHP) FOLLOWING SPIKE BURSTS IN HIPPOCAMPAL PYRAMIDAL CELLS. Fulltekst i vitenarkiv Vis sammendrag

  In hippocampal pyramidal cells, a burst of action potentials (APs) is followed by medium (mAHP, lasting ~0.1s). During AP trains, the currents underlying these AHPs cause early spike frequency adaptation. The mAHP was originally suggested to be primarily caused by M-current (at depolarized potentials) and H-current (at more negative potentials), with a minor contribution from BK channels, but not measurably from SK channels (Storm 1989, J.Physiol 409:171-90). Later, however, the mAHP was suggested to be generated by SK channels (Stocker et al., 1999, PNAS 96:4662) or mainly H channels (Maccaferri et al. J Neurophysiol 69:2129). We have now reexamined the mAHP in CA1 pyramidal cells in rat hippocampal slices, using whole cell patch and sharp electrode intracellular recordings, while holding the cell at different potentials by steady current injection. M-channel blockade by XE991 (10 uM) suppressed the mAHP following bursts of 5 APs, evoked by current pulses, at �60mV, but had no measurable effect at at �80mV. In contrast, the H-channel blocker ZD7288 (10 uM) had no measurable effect at �60mV but blocked the mAHP at �80mV. The SK channel blockers apamin (100-400nM) and d-tubocurarine (dTC; 100uM) failed to reliably reduce the mAHP at all conditions tested: at -60 and -80 mV, after of 5 APs at 30oC, and after 400ms spike trains at room temperature (Stocker et al 1999), although these blockers reliably prolonged Ca2+ spikes evoked in TTX. In voltage-clamp, apamin and d-TC reliably blocked an early component of the Ca2+-dependent tail current ( Sailer CA et al. J Neurosci 2002 22:9698). A computational model if a CA1 puramidal cell (Hu et al. 2002) predicted that M and H channels will generate mAHPs in a voltage-dependent manner, as indicated by the experiments. We conclude that M- and H-channels generate the post-burst mAHP in hippocampal pyramidal cells, with little or no contribution from SK channels. [Supported by the Norwegian Research Council and EU]

• Storm, Johan Fredrik; Vervaeke, Koen Gerard Alois & Hu, Hua (2002). M- and H-current contribute to subthreshold electrical resonance at theta frequencies in rat CA1 hippocampal pyramidal neurons. Fulltekst i vitenarkiv Vis sammendrag

  Coherent network oscillations in the brain are correlated with different behavioral states. Intrinsic resonance properties of neurons provide a basis for such oscillations. In the hippocampus, CA1 pyramidal neurons show resonance at theta frequencies (2-7 Hz). To study the mechanisms underlying theta-resonance, we performed whole-cell recordings from CA1 pyramidal cells (n=64) in rat hippocampal slices. Oscillating current injections at different frequencies (ZAP protocol), revealed clear resonance with peak impedance at 2-5 Hz. The theta-resonance showed a U-shaped voltage-dependence, being strong at subthreshold depolarized (~-60mV) and hyperpolarized (~-80mV) potentials, but weaker near the resting potential (-72mV). Voltage clamp experiments revealed three non-inactivating currents operating in the subthresold voltage range: (1) M-current (IM), which activated positive to �65mV and was blocked by the M/KCNQ-channel blocker XE991 (10&#956;M). (2) h-current (Ih), which activated negative to �65mV and was blocked by the h/HCN-channel blocker ZD7288 (10&#956;M), and (3) a persistent Na+ current (INaP), which activated positive to �65mV and was blocked by tetrodotoxin (TTX, 1&#956;M). In current clamp, XE991 or TTX suppressed the resonance at depolarized, but not hyperpolarized membrane potentials, whereas ZD7288 abolished the resonance only at hyperpolarized potentials. We conclude that these cells show two forms of theta-resonance: �M-resonance� generated by M-current and persistent Na+ current in depolarized cells, and �h-resonance� generated by h-current in hyperpolarized cells. Computer simulations supported this interpretation. These results suggest a novel function for M-/KCNQ-channels in the brain: to facilitate neuronal resonance and network oscillations in cortical neurons, thus supporting an oscillation-based neural code.

• Hu, Hua & Storm, Johan Frederik (2005). Functions of Ca2+ -activated and KCNQ/M-type potassium channels in the brain. Universitetet i Oslo. ISSN 9788280722065. Fulltekst i vitenarkiv

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