Available online at www.sciencedirect.com

Plasticity of voltage-gated ion channels in S Remy1,2, H Beck1 and Y Yaari3,4

Dendrites of pyramidal integrate multiple synaptic particularly interesting compartments where local inputs and transform them into axonal output. changes in intrinsic excitability can occur. Indeed, in This fundamental process is controlled by a variety of dendritic some paradigms, intrinsic neuronal and channels. The properties of dendritic ion channels are not static can be induced simultaneously in the same compartment but can be modified by neuronal activity. Activity-dependent [3,4]. changes in the density, localization, or biophysical properties of dendritic voltage-gated channels can persistently alter the Pyramidal neurons integrate synaptic inputs that are integration of synaptic inputs. Furthermore, dendritic intrinsic widely distributed across the extent of the dendritic plasticity can induce neuronal output mode transitions (e.g. arborization. The magnitude of the local voltage deflec- from regular spiking to burst firing). Recent advances in the field tion at the , and how it propagates to the action reviewed here represent an important step toward uncovering potential initiation zone at the initial segment and the principles of neuronal input/output transformations in the first [5,6], is strongly determined by response to various patterns of activity. both the passive properties of the dendritic tree and the Addresses active dendritic conductances [7]. The pattern of axonal 1 Department of Epileptology, University of Bonn Medical Center, output also depends on the properties of local axonal D-53105 Bonn, Germany conductances that transduce the dendritic signals into 2 German Center for Neurodegenerative Diseases (DZNE), D-53127, axonal spiking. Accordingly, plastic changes in the Bonn, Germany density, localization, or biophysical properties of dendritic 3 Department of Medical Neurobiology, Institute of Medical Research Israel-Canada, Hebrew University-Hadassah School of Medicine, channels, can persistently alter neuronal integration and Jerusalem 91120, Israel induce neuronal output mode transitions (e.g. from 4 The Interdisciplinary Center for Neuronal Computation, the Hebrew regular spiking to burst firing). University, Jerusalem 91904, Israel

Corresponding author: Yaari, Y ([email protected]) The active properties of dendrites and their plasticity have been particularly well studied in pyramidal cells. These dendrites express a plethora of voltage-dependent Current Opinion in Neurobiology 2010, 20:503–509 ionic conductances with a branch-specific expression pattern, conferring strongly nonlinear properties on den- This review comes from a themed issue on dritic subsegments. In particular, clustered and synchro- Signalling mechanisms Edited by Linda van Aelst and Pico Caroni nous excitatory synaptic inputs can trigger local, nonlinear ‘all or nothing’ at some branches, referred Available online 4th August 2010 to as dendritic spikes [8]. These spikes propagate from 0959-4388/$ – see front matter their dendritic initiation site toward the axon, where they # 2010 Elsevier Ltd. All rights reserved. can trigger axonal spikes. In this way, the spatial and temporal synchrony of synaptic inputs strongly influence DOI 10.1016/j.conb.2010.06.006 neuronal spike output [9].

Here, we review the most recent advances regarding the Introduction intrinsic plasticity of pyramidal cell dendrites induced by physiological and pathophysiological stimuli and discuss Physiological and abnormal bouts of neuronal activity can its impact on neuronal integration and spike output mode. induce persistent changes in the expression level and/or biophysical properties of ionic channels in the dendritic and axosomatic membranes of hippocampal and cortical Distribution of voltage-gated ion channels in pyramidal neurons, thereby modifying their intrinsic pyramidal cell dendrites properties [1]. In rodents, such intrinsic neuronal Our knowledge about the distribution of voltage-gated plasticity occurs during or exposure to enriched ion channels in pyramidal cell dendrites stems mainly environment, as well as during sensory deprivation or from direct dendritic patch-clamp recordings and immu- status epilepticus [2]. It is also readily induced in vitro, nolocalization of their underlying subunits [10]. Cell- using stimulation patterns mimicking normal brain attached patch-clamp recordings and freeze-fracture elec- activity. As is the case of synaptic plasticity, neuronal tron microscopy have revealed a more or less uniform dendrites or dendritic subsegments are emerging as voltage-gated Na+ channel density in the apical trunk of www.sciencedirect.com Current Opinion in Neurobiology 2010, 20:503–509 504 Signalling mechanisms

pyramidal neurons [11,12], which is sufficient for gener- inputs and the storage of information. One important ating dendritic Na+ spikes [13]. Several voltage-gated function of dendritic ion channels is regulating the integ- Ca2+ channel types have also been observed in these ration of subthreshold synaptic potentials (EPSPs and dendrites, including the low voltage-gated T-type and IPSPs) and their influence on membrane potential at the the high voltage-gated L-type, P/Q-type, N-type and site of action potential initiation (see [7] for a detailed R-type Ca2+ channels [11,14]. In CA1 pyramidal neurons, review). In addition, dendritic voltage-gated channels are the densities of T-type and R-type Ca2+ channels appear important in the generation of dendritic spikes, regen- to be highest in the distal dendrites, whereas L-type and erative events initiated by strong, correlated synaptic N-type channels are more abundant in the proximal inputs. Direct dendritic patch-clamp recordings from dendritic regions [11,14–16]. Among several functions, hippocampal and layer 5 neocortical pyramidal cells have activation of dendritic Ca2+ channels provides additional confirmed that the main apical dendrites are capable of to excitatory postsynaptic potentials generating dendritic spikes mediated by voltage-gated (EPSPs) and links dendritic signal integration to intra- Na+ channels, Ca2+ channels and NMDA receptor chan- cellular signaling cascades. Another group of channels nels and curtailed by transient A-type K+ channels present at higher densities on the distal main apical [9,13,23,24]. dendrites in both neocortical layer V and CA1 pyramidal neurons are the hyperpolarization-activated channels Two recent technological improvements, namely, i) the (HCN) [17,18]. These channels are partially activated use of gradient-scanning confocal microscopy to visually   at resting potential, generating an inward current, Ih. aid dendritic patch-clamp recordings [22 ,25 ], and ii) the Deactivation of Ih reduces EPSPs duration, while its introduction of two-photon glutamate uncaging, have now activation reduces the duration of inhibitory post synaptic allowed to probe the integrative properties of even the potentials (IPSPs). Therefore, this current strongly smallest dendrites of the brain at unprecedented detail affects the temporal summation of synaptic signals. [9,26]. Using these techniques, the excitability of small The somatodendritic gradient and biophysical properties diameter branches, such as basal dendrites, radial oblique of HCN channels reduce the location dependence of branches, and apical tufts, has recently been successfully synaptic integration for a wide range of spatiotemporal examined. These studies have shown that small diameter input patterns [19]. Another prominent group of dendritic dendritic branches possess voltage-gated conductances channels, the A-type K+ channels, underlie a rapidly that support the generation and propagation of local den- + activating and inactivating K current (IA). They are also dritic spikes. Nevian et al. were the first to establish dual expressed with an increasing somatodendritic gradient in somatic and dendritic patch-clamp recordings from basal CA1 pyramidal neurons [23], whereas layer V pyramidal dendrites of layer V pyramidal cells [22]. They found that neurons show a uniform somatodendritic distribution these dendrites possess the ionic machinery to generate [20,21]. In the former neurons, the several-fold higher fast Na+ spikes and NMDA receptor-mediated spikes, but density of these channels at the distal part of the main lack Ca2+ spikes. Subsequently this technique was success- apical dendrites compared to the , is thought to fully used on apical tuft dendritic branches [25]. These function as a neuronal ‘shock absorber’, limiting the branches were also capable of triggering Na+ and NMDA spread of backpropagating action potentials into the den- receptor-mediated spikes, whereas Ca2+ spikes seemed to dritic tree and curtailing dendritic spikes [9,21]. The originate from a distinct initiation zone several hundred density of sustained K+ current components along the micrometers away from the soma. The authors proposed a somatodendritic axis remains relatively constant. unifying view of integration in layer 5 pyramidal cells, in which all fine dendrites, basal and tuft, integrate inputs Much is known about the identity and general distri- locally through recruitment of NMDA receptor-mediated bution patterns of voltage-gated ion channels in the main dendritic spikes, whereas fixed integration zones exist for apical trunk of different classes of pyramidal neurons. dendritic Ca2+ spikes and axonal spike initiation [25]. However, our knowledge of the electrical properties and Whether this principle is applicable to hippocampal pyr- their underlying ionic conductances at fine dendritic amidal neurons is not yet known. branches, which receive the majority of synaptic inputs, is quite limited. Improved electrophysiological [22] and Plasticity of dendritic branch strength immunolocalization techniques [12] hold promise to elu- Can the excitability of individual dendritic branches be cidate the principles governing the diversity in ion chan- adjusted by excitatory synaptic activity, and if so, what nel distributions between individual neurons and within does it imply for the conversion of synaptic input to spike fine dendritic branches of individual neurons. output? Stimulation patterns used to induce long-term potentiation (LTP) of EPSPs have been shown also to Nonlinear integration in pyramidal cell induce specific changes in the properties of voltage-gated dendrites ion channels expressed on main apical CA1 dendrites. Voltage-gated channels in dendrites of pyramidal neurons For instance, dendritic A-type currents were shown to play an important role in both the processing of synaptic be persistently downregulated, resulting in increased

Current Opinion in Neurobiology 2010, 20:503–509 www.sciencedirect.com Plasticity of voltage-gated ion channels in pyramidal cell dendrites Remy, Beck and Yaari 505

dendritic excitability [27]. A spatially restricted mechan- et al. has shown that this may indeed be the case. In the ism for this form of plasticity has been suggested from presence of cholinergic agonists, ‘weak’ branches were work in hippocampal pyramidal cultures, invol- converted to strongly spiking branches by pairing synap- ving the rapid, local clathrin-mediated internalization of tic excitation with postsynaptic action potential firing. Kv4.2 (A-type) channel subunits. This mechanism This conversion resulted in an improved propagation of appears to require NMDA receptor activation [28,29]. locally elicited dendritic spikes to the soma, probably owing to local downregulation of dendritic A-type K+ To examine intrinsic plasticity induced by excitatory currents [30]. The relevance of these findings to beha- synaptic activity at small higher order dendrites, and to vioral brain plasticity has recently been supported by the determine its spatial extent, a precise control over the same group. It was shown that CA1 pyramidal cells from region of synapse activation is required. Two-photon animals maintained in an enriched environment dis- glutamate uncaging now permits a precise release of played a facilitated propagation of dendritic spikes in a glutamate at single or multiple spines. This technique subset of dendritic branches [31]. can be used to probe the properties of all neuronal compartments including higher order and terminal den- Contribution of dendritic conductances to dritic branches. Dendritic spikes evoked in this way on intrinsic burst firing CA1 basal and radial oblique branches always consisted of Extracellular single-unit recordings in vivo have shown a fast Na+ spike, followed by a slow depolarization, that neocortical and hippocampal neurons fire in a solitary mediated by NMDA receptor and Ca2+ currents spike mode or in a burst mode [32]. However, the [9,26]. Interestingly, dendritic branches showed a bimo- contribution of intrinsic factors to burst firing in CA1, dal distribution, with one population of branches respond- CA3, subicular, and cortical pyramidal cells has been ing weakly and the other strongly to synchronous synaptic examined thoroughly only in slice preparations in vitro. stimulation ([30], see Figure 1). These data suggest that Both dendritic and axosomatic conductances have been information in neurons may not only be stored as synaptic shown to be promote burst firing in these neurons [2]. weights of input synapses. Rather, active dendritic These conductances control, by different mechanisms, branches may serve to detect specific features of input the amplitude of the somatic spike after-depolarization (i.e. synchrony). But can these intrinsic branch properties (ADP), which in turn determines whether the threshold be modified by activity? An elegant study by Losonczy for generating additional action potentials is crossed. In

Figure 1

Intrinsic plasticity of dendritic branch strength. Dendritic spikes occur when dendritic branches of CA1 pyramidal neurons receive spatially clustered and synchronous excitatory synaptic input. Using two-photon uncaging of MNI-glutamate on several spines (red and blue dots on A and B), dendritic spikes could be reliably evoked by Losonczy et al. [30]. When recorded at the soma, dendritic spikes could be divided into two groups depending on the dV/dt of their somatic voltage deflection (Panel A and B from [30]). Weak spikes led to a nonlinear increase in intradendritic calcium locally at the site of initiation (a), strong spikes actively propagated, resulting in a calcium elevation also on their path to the soma (b). (c) Schematic representation of branch strength potentiation. Theta pairing protocol (one uncaging-evoked dendritic branch spike paired repetitively with 2–3 backpropagating action potentials at theta frequency) induced an increase in branch strength over time (increase in dV/dt of the somatic voltage deflection). A similar upregulation could be achieved in the stimulated branch by bath perfusion of the muscarinic agonist carbachol (5 mM) together with repetitive dendritic spiking, but not by dendritic spikes alone (adapted by permission from Macmillan Publishers Ltd. Nature from [30], copyright 2008). The question mark indicates that no mechanism for a downregulation of branch strength has been found so far. www.sciencedirect.com Current Opinion in Neurobiology 2010, 20:503–509 506 Signalling mechanisms

most adult pyramidal cells, the somatic spike ADP is dendritic spikes can be evoked by strong excitatory driven predominantly by persistent Na+ current [33] and synaptic inputs as discussed above, or nonsynaptically is ordinarily maintained subthreshold by coactivation of by backpropagating action potentials. Somatic bursting the M-type K+ current [34]. However, generation of caused by backpropagating action potentials was demon- dendritic spikes and their propagation to the soma can strated in immature [35,36], as well as in adult CA1 boost this afterpotential, resulting in burst firing. These pyramidal cells that experienced pilocarpine-induced

Figure 2

Altered firing mode due to altered dendritic excitability in CA1 pyramidal cells after pilocarpine-induced status epilepticus (SE). Control neurons (top panels) respond to prolonged current injections with a series of independent action potentials (left panel), and to brief current injections with a single action potential (right panel). SE-experienced neurons (bottom panels) respond to brief or prolonged current injection with an all-or-nothing high- frequency action potential burst [45]. (b) Aberrant intrinsic bursting in SE-experienced neurons is driven by dendritic Ca2+ channels sensitive to low concentrations of Ni2+. Bursting is blocked by focal application of 30–100 mMNi2+ to the dendrites, but not to the somatic region [41]. (c) Upregulation of Cav3.2 expression in apical dendrites of SE-experienced CA1 pyramidal cells. Top panels: specimen from sham-control rat; bottom panels: specimen from SE-experienced rat (5 days after SE). From left to right: immunostaining with CaV3.2 antibodies (red); immunostaining with MAP2 antibodies to visualize apical dendrites (green); overlay of CaV3.2 and MAP2 immunostainings. Note the strongly increased immunostaining of Cav3.2 2+ in MAP2-positive dendrites. Scale bar, 100 mm[46]. (d) CaV3.2 upregulation underlies increased T-type Ca currents in CA1 neurons after SE. Top panel: Representative examples of T-type Ca2+ currents in neurons from control and SE-experienced rats. The voltage protocol used to elicit the 2+ +/+ currents is shown on top. Bottom panel: Quantification of the magnitude of T-type Ca currents reveals a significant 2.2-fold increase in CaV3.2 À/À (wildtype) mice but not in CaV3.2 (knockout) mice. (e) Flow diagram of SE-evoked events supposedly leading to de novo intrinsic burst firing of CA1 pyramidal neurons and consequent epileptogenic functional and morphological network alterations (see text for further description).

Current Opinion in Neurobiology 2010, 20:503–509 www.sciencedirect.com Plasticity of voltage-gated ion channels in pyramidal cell dendrites Remy, Beck and Yaari 507

status epilepticus (SE) [35,36] or were acutely exposed to firing in response to a given spatial and temporal input the A-type K+ channel blocker 4-aminopyridine [37]. In pattern. A question that clearly has to be resolved before all these cases it was shown that the backpropagating is the following: What are the in vivo input patterns of action potentials triggered apical dendritic Ca2+ spikes. activity a dendrite receives during physiological (e.g. a Congruently, bursting in all these neurons was readily learning paradigm) and pathophysiological behavior (e.g. suppressed by Ca2+ channel blockers focally applied to an epileptic seizure). Optical and electrophysiological in the apical dendrites [40–42]. vivo recordings with subcellular resolution can confirm whether observation made in brain slices are also relevant Plasticity of dendritic conductances for the in vivo situation. These techniques have already contributing to intrinsic burst firing been successfully introduced and may be used more The molecular mechanisms underlying the emergence of commonly in the future [46–48]. Of equal importance Ca2+-dependent bursting in CA1 pyramidal cells follow- will be a precise understanding of the neural circuits ing pilocarpine-induced SE has been intensively inves- generating the spatial and temporal input patterns on tigated [38,39]. An upregulation of a Ni2+ sensitive T- the dendritic tree (e.g. layered excitatory input, feedfor- type current in the apical dendrites was previously impli- ward and feedback inhibition and neuromodulatory cated in this phenomenon [40]. Recently, Becker et al. input). Novel optogenetic tools now allow functional demonstrated a transient transcriptional upregulation of input mapping and cell specific manipulation of circuits 2+ 2+ the Ni sensitive T-type Ca channel subunit Cav3.2 [49,50]. In addition, serial scanning electron microscopy beginning within a few days after SE. Mice with genetic may serve as powerful tool to spatially reconstruct the deletions of Cav3.2 did not show the upregulation of T- individual synaptic input of a neuron and the underlying type Ca2+ current and associated bursting behavior, prov- circuitry [51,52].  ing its crucial dependence on CaV3.2 upregulation [41 ]. Changes in other dendritic conductances, such as down- Acknowledgements regulation of HCN [42] and A-type K+ channels [43] have Supported by the German-Israel Foundation (GIF), the Deutsche Forschungsgemeinschaft SFB TR3, NGFNplus, the Ministry for been described in this and in other SE models, and may Innovation, Science, Research and Technology of Nordrhein-Westfalen and 2+ facilitate the emergence of Ca -dependent bursting. It the Henri J. and Erna D. Leir Chair for Research in Neurodegenerative would be highly desirable to specifically identify the Diseases. transcriptional regulatory mechanisms underlying these ‘channelopathies’ that are responsible for inducing and References and recommended reading Papers of particular interest, published within the period of review, maintaining altered expression of voltage-gated ion chan- have been highlighted as: nels (Figure 2).  of special interest  of outstanding interest In a recent study in the barrel cortex, the group of Stuart demonstrated that sensory deprivation caused by whisker 1. Zhang W, Linden DJ: The other side of the engram: experience- trimming led to an increase in the fraction of bursting driven changes in neuronal intrinsic excitability. Nat Rev layer 5 pyramidal neurons [44]. This plasticity was Neurosci 2003, 4:885-900. associated with a reduction in the threshold for generation 2. Beck H, Yaari Y: Plasticity of intrinsic neuronal properties in CNS disorders. Nat Rev Neurosci 2008, 9:357-369. of dendritic Ca2+ spikes evoked by backpropagating action potentials. The authors suggested that the under- 3. Rosenkranz JA, Frick A, Johnston D: Kinase-dependent modification of dendritic excitability after long-term lying mechanism is downregulation of HCN channel potentiation. J Physiol 2009, 587:115-125. density in distal regions of the apical dendrites. Recently 4. Chen X, Yuan LL, Zhao C, Birnbaum SG, Frick A, Jung WE, also, a persistent increase in the propensity for bursting in Schwarz TL, Sweatt JD, Johnston D: Deletion of Kv4.2 gene eliminates dendritic A-type K+ current and enhances induction subicular neurons has been shown to occur in vitro follow- of long-term potentiation in hippocampal CA1 pyramidal ing various modes of synaptic excitation and metabotropic neurons. J Neurosci 2006, 26:12143-12151. receptor activation, but a distinct role for dendritic con- 5. Jefferys JG: Initiation and spread of action potentials in granule ductances has not been ascribed to this plasticity [45]. cells maintained in vitro in slices of guinea-pig . J Physiol 1979, 289:375-388. Concluding remarks 6. Stuart G, Spruston N, Sakmann B, Hausser M: Action potential initiation and backpropagation in neurons of the mammalian The recent discoveries reviewed here represent a step CNS. Trends Neurosci 1997, 20:125-131. further toward understanding the role dendrites play in 7. Spruston N: Pyramidal neurons: dendritic structure and the transformation of synaptic input into neuronal output synaptic integration. Nat Rev Neurosci 2008, 9:206-221. in pyramidal cells. As we learn more about the function of 8. Hausser M, Spruston N, Stuart GJ: Diversity and dynamics of small diameter dendritic branches, we move toward the dendritic signaling. Science 2000, 290:739-744. goal of defining rules for the input/output integration in 9. Losonczy A, Magee JC: Integrative properties of radial oblique these principal neurons. It seems possible that at some  dendrites in hippocampal CA1 pyramidal neurons. Neuron 2006, 50:291-307. point we may be able to predict under which conditions a The authors show for the first time that two-photon uncaging of glutamate neuron will fire single action potentials or exhibit burst is a very useful tool for investigating signal integration in small diameter www.sciencedirect.com Current Opinion in Neurobiology 2010, 20:503–509 508 Signalling mechanisms

dendritic branches of CA1 pyramidal neurons. It explores both the spatial 28. Hammond RS, Lin L, Sidorov MS, Wikenheiser AM, Hoffman DA: and temporal input requirements for dendritic spike generation and the Protein kinase a mediates activity-dependent Kv4.2 channel conductances underlying spikes in radial oblique branches. trafficking. J Neurosci 2008, 28:7513-7519. 10. Trimmer JS, Rhodes KJ: Localization of voltage-gated ion 29. Kim J, Jung SC, Clemens AM, Petralia RS, Hoffman DA: channels in mammalian brain. Annu Rev Physiol 2004, Regulation of dendritic excitability by activity-dependent + 66:477-519. trafficking of the A-type K channel subunit Kv4.2 in hippocampal neurons. Neuron 2007, 54:933-947. 11. Magee JC, Johnston D: Characterization of single voltage- gated Na+ and Ca2+ channels in apical dendrites of rat CA1 30. Losonczy A, Makara JK, Magee JC: Compartmentalized pyramidal neurons. J Physiol 1995, 487(Pt 1):67-90.  dendritic plasticity and input feature storage in neurons. Nature 2008, 452:436-441. 12. Lorincz A, Nusser Z: Molecular identity of dendritic voltage- Losonczy et al. show that the coupling between local dendritic spikes and gated sodium channels. Science 2010, 328:906-909. the soma of rat hippocampal CA1 pyramidal neurons can be modified in a 13. Golding NL, Spruston N: Dendritic sodium spikes are variable branch-specific manner through an NMDA receptor-dependent regula- triggers of axonal action potentials in hippocampal CA1 tion of dendritic Kv4.2 potassium channels. This intrinsic dendritic plas- pyramidal neurons. Neuron 1998, 21:1189-1200. ticity could store spatio-temporal features of synaptic input. 14. Christie BR, Eliot LS, Ito K, Miyakawa H, Johnston D: Different 31. Makara JK, Losonczy A, Wen Q, Magee JC: Experience- Ca2+ channels in soma and dendrites of hippocampal dependent compartmentalized dendritic plasticity in rat pyramidal neurons mediate spike-induced Ca2+ influx. J hippocampal CA1 pyramidal neurons. Nat Neurosci 2009, Neurophysiol 1995, 73:2553-2557. 12:1485-1487. 15. Stuart GJ, Sakmann B: Active propagation of somatic action 32. Harris KD, Hirase H, Leinekugel X, Henze DA, Buzsaki G: potentials into neocortical pyramidal cell dendrites. Nature Temporal interaction between single spikes and complex 1994, 367:69-72. spike bursts in hippocampal pyramidal cells. Neuron 2001, 32:141-149. 16. Kavalali ET, Zhuo M, Bito H, Tsien RW: Dendritic Ca2+ channels 33. Yue CY, Remy S, Su HL, Beck H, Yaari Y: Proximal persistent characterized by recordings from isolated hippocampal + dendritic segments. Neuron 1997, 18:651-663. Na channels drive spike afterdepolarizations and associated bursting in adult CA1 pyramidal cells. J Neurosci 17. Lorincz A, Notomi T, Tamas G, Shigemoto R, Nusser Z: Polarized 2005, 25:9704-9720. and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat Neurosci 2002, 5:1185-1193. 34. Yue CY, Yaari Y: KCNQ/M channels control spike afterdepolarization and burst generation in hippocampal 18. Magee JC: Dendritic hyperpolarization-activated currents neurons. J Neurosci 2004, 24:4614-4624. modify the integrative properties of hippocampal CA1 2+ pyramidal neurons. J Neurosci 1998, 18:7613-7624. 35. Chen SM, Yue CY, Yaari Y: A transitional period of Ca - dependent spike afterclepolarization and bursting in 19. Magee JC: Dendritic lh normalizes temporal summation in developing rat CA1 pyramidal cells. J Physiol-Lond 2005, hippocampal CA1 neurons. Nat Neurosci 1999, 2:508-514. 567:79-93. 20. Bekkers JM: Distribution and activation of voltage-gated 36. Yaari Y, Yue CY, Su HL: Recruitment of apical dendritic T-type potassium channels in cell-attached and outside-out patches Ca2+ channels by backpropagating spikes underlies de novo from large layer 5 cortical pyramidal neurons of the rat. J intrinsic bursting in hippocampal epileptogenesis. J Physiol- Physiol 2000, 525(Pt 3):611-620. Lond 2007, 580:435-450. 21. Hoffman DA, Magee JC, Colbert CM, Johnston D: K+ channel 37. Magee JC, Carruth M: Dendritic voltage-gated ion channels regulation of signal propagation in dendrites of hippocampal regulate the action potential firing mode of hippocampal CA1 pyramidal neurons. Nature 1997, 387:869-875. pyramidal neurons. J Neurophysiol 1999, 82:1895-1901. 22. Nevian T, Larkum ME, Polsky A, Schiller J: Properties of basal 38. Azouz R, Jensen MS, Yaari Y: Ionic basis of spike after-  dendrites of layer 5 pyramidal neurons: a direct patch-clamp depolarization and burst generation in adult rat hippocampal recording study. Nat Neurosci 2007, 10:206-214. CA1 pyramidal cells. J Physiol 1996, 492(Pt 1):211-223. In this paper, gradient-scanning two-photon imaging was used to record for the first time directly from small diameter dendritic branches of 39. Jensen MS, Azouz R, Yaari Y: Spike after-depolarization and pyramidal neurons and to explore their integrative properties. burst generation in adult rat hippocampal CA1 pyramidal cells. J Physiol 1996, 492(Pt 1):199-210. 23. Wong RK, Prince DA, Basbaum AI: Intradendritic recordings from hippocampal neurons. Proc Natl Acad Sci USA 1979, 40. Su H, Sochivko D, Becker A, Chen J, Jiang Y, Yaari Y, Beck H: 76:986-990. Upregulation of a T-type Ca2+ channel causes a long-lasting modification of neuronal firing mode after status epilepticus. J 24. Stuart G, Schiller J, Sakmann B: Action potential initiation and Neurosci 2002, 22:3645-3655. propagation in rat neocortical pyramidal neurons. J Physiol 1997, 505(Pt 3):617-632. 41. Becker AJ, Pitsch J, Sochivko D, Opitz T, Staniek M, Chen CC,  Campbell KP, Schoch S, Yaari Y, Beck H: Transcriptional 25. Larkum ME, Nevian T, Sandler M, Polsky A, Schiller J: Synaptic upregulation of Cav3.2 mediates epileptogenesis in the  integration in tuft dendrites of layer 5 pyramidal neurons: a pilocarpine model of epilepsy. J Neurosci 2008, 28:13341- new unifying principle. Science 2009, 325:756-760. 13353. In this paper, two-photon guided whole-cell patch-clamp recordings This paper shows that transcriptional upregulation of the dendritic T-type 2+ were applied to the small diameter tuft dendrites of layer 5 neocortical Ca channel subunit CaV3.2, induced by status epilepticus (SE), causes pyramidal neurons. It revealed that tuft dendrites support the generation a transitional increase in intrinsic burst firing, and probably is a crucial of NMDA spikes. Through this mechanism distal synaptic inputs can step in SE-induced epileptogenesis and neuronal cell death. trigger the firing of these neurons. 42. Jung S, Jones TD, Lugo JN Jr, Sheerin AH, Miller JW, 26. Remy S, Csicsvari J, Beck H: Activity-dependent control of D’Ambrosio R, Anderson AE, Poolos NP: Progressive dendritic  neuronal output by local and global dendritic spike HCN channelopathy during epileptogenesis in the rat attenuation. Neuron 2009, 61:906-916. pilocarpine model of epilepsy. J Neurosci 2007, 27:13012-13021. This paper shows how slow cumulative inactivation of sodium channels causes attenuation and failure of dendritic spikes. This mechanism can be 43. Bernard C, Anderson A, Becker A, Poolos NP, Beck H, Johnston D: invoked by strong synaptic inputs and by backpropagatng axonal action Acquired dendritic channelopathy in temporal lobe epilepsy. potentials at frequencies encountered during learning. Science 2004, 305:532-535. 27. Frick A, Magee J, Johnston D: LTP is accompanied by an 44. Breton JD, Stuart GJ: Loss of sensory input increases the enhanced local excitability of pyramidal neuron dendrites. Nat  intrinsic excitability of layer 5 pyramidal neurons in rat barrel Neurosci 2004, 7:126-135. cortex. J Physiol 2009, 587:5107-5119.

Current Opinion in Neurobiology 2010, 20:503–509 www.sciencedirect.com Plasticity of voltage-gated ion channels in pyramidal cell dendrites Remy, Beck and Yaari 509

In this study, sensory deprivation caused by whisker trimming led to an 48. Grewe BF, Helmchen F: Optical probing of neuronal ensemble increase in the fraction of bursting layer 5 pyramidal neurons underlain by activity. Curr Opin Neurobiol 2009, 19:520-529. an apical dendritic downregulation of HCN channel density. 49. Petreanu L, Mao TY, Sternson SM, Svoboda K: The subcellular 45. Moore SJ, Cooper DC, Spruston N: Plasticity of burst organization of neocortical excitatory connections. Nature firing induced by synergistic activation of metabotropic 2009, 457:1142-2100. glutamate and acetylcholine receptors. Neuron 2009, 61:287-300. 50. Zhang F, Aravanis AM, Adamantidis A, de Lecea L, Deisseroth K: Circuit-breakers: optical technologies for probing neural 46. Epsztein J, Lee AK, Chorev E, Brecht M: Impact of spikelets on signals and systems. Nat Rev Neurosci 2007, 8:577-581. hippocampal CA1 pyramidal cell activity during spatial 51. Denk W, Horstmann H: Serial block-face scanning electron exploration. Science 2010, 327:474-477. microscopy to reconstruct three-dimensional tissue 47. Murayama M, Perez-Garci E, Luscher HR, Larkum ME: nanostructure. PLoS Biol 2004, 2:1900-1909. Fiberoptic system for recording dendritic calcium signals 52. Jurrus E, Hardy M, Tasdizen T, Fletcher PT, Koshevoy P, Chien CB, in layer 5 neocortical pyramidal cells in freely moving rats. Denk W, Whitaker R: Axon tracking in serial block-face scanning J Neurophysiol 2007, 98:1791-1805. electron microscopy. Med Image Anal 2009, 13:180-188.

www.sciencedirect.com Current Opinion in Neurobiology 2010, 20:503–509