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Roles of ion channels in EPSP integration at neuronal dendrites
Neuroscience Research 37 (2000) 167 – 171 www.elsevier.com/locate/neures
Update Article
Roles of ion channels in EPSP integration at neuronal dendrites Hiroshi Takagi * Department of Neuroplasticity, Research Center for Aging and Adaptation, Shinshu Uni6ersity School of Medicine, Matsumoto, Nagano 390 -8621, Japan Received 23 February 2000; accepted 23 March 2000
Abstract Many different kinds of voltage-gated ion channels (Na+ channels, K+ channels, Ca2 + channels) exist at neuronal dendrites. Integration of dendritic electric signals (excitatory postsynaptic potentials (EPSPs), inhibitory postsynaptic potentials (IPSPs) and action potentials) and/or non-electric signals (Ca2 + and second messengers) occurs in restricted dendritic compartments consisting of spines and adjacent fine dendrites. Voltage-gated ion channels at neuronal dendrites play crucial roles in the integration of dendritic signals. Dendritic signals, in turn, play important roles in the modulation of local dendritic physiological functions (e.g. input-specific synaptic plasticity, long-term potentiation (LTP) and long term depression (LTD)). A combined experimental and theoretical approach is a good way to clarify the biophysical behaviors of dendritic ion channels. Analyses of dendritic ion channels can open the door to a new wave of discoveries about EPSP integration at neuronal dendrites. © 2000 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved. Keywords: Dendritic integration; Na+ channels; Ca2 + channels; K+ channels; Computer simulation; Cable theory
1. Introduction A central aspect of neuronal function is to translate synaptic inputs into a sequence of action potentials that carry information along the axon, coded temporarily and/or coded as spike frequency. Cable filtering of the synaptic currents reduces the amplitude of excitatory and/or inhibitory postsynaptic potentials (EPSPs and/ or IPSPs) and limits spatial summation among distributed synapses (so-called dendritic integration), strongly regulating the impact of many synapses on neuronal outputs (Jaslove, 1992; Spruston et al., 1993, 1994). For most of the 20th century, neuronal dendrites were considered to be passive cables satisfying cable equations (Rall, 1997). This view was challenged in the 1960s by reports of dendritic action potentials in cerebral pyramidal cells (Spencer and Kandel, 1961) and cerebellar Purkinje cells (Llina´s et al., 1968). Recently, many kinds of neuronal dendrites, such as hippocampal * Tel.: +81-263-372728; fax: + 81-263-372725. E-mail address: [email protected] (H. Takagi).
pyramidal cells and cerebral cortical pyramidal cells, have been confirmed to be ‘active’ cables that do not necessarily satisfy passive cable theory. Neuronal dendrites contain a variety of voltage-gated ion channels that enable action potentials and EPSPs to propagate actively throughout the neuron (Johnston et al., 1996; Yuste and Tank, 1996). For example, voltage-gated Ca2 + channels are mainly expressed in the dendritic regions of cerebellar Purkinje cells, while voltage-gated Na+ channels are widely expressed in the dendritic regions of cerebral cortical pyramidal cells (Llina´s and Sugimori, 1980b; Stuart and Sakmann, 1994). Activation of these dendritic voltage-gated ion channels, following the integration of many synaptic inputs (EPSP integration), produces plateau and spiky local potentials in the dendritic regions. These local potentials induce a rise in local intracellular Ca2 + concentration ([Ca2 + ]i), which modulates Ca2 + -activated ion channels and drives Ca2 + -activated signal transduction systems. Because synaptic activation can induce the production of postsynaptic electrical signals and intracellular biochemical events such as the generation of
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second messengers, EPSP integration may be affected by second messengers (Bourne and Nicoll, 1993). One of the most remarkable findings of recent years is the demonstration of highly localized Ca2 + transients that are limited to small dendritic segments and even to single dendritic spines (Eilers and Konnerth, 1997). In addition, by use of a two-photon excitation imaging technique it has been possible to reveal the existence of dendritic Ca2 + signals even in the neocortical pyramidal cells of anaesthetized rats (Svoboda et al., 1997). These local physiological changes may induce local dendritic functional modulations, such as input-specific synaptic plasticity (Alger and Teyler, 1976; Andersen et al., 1977). This article describes recent data regarding the various types of voltage-gated Na+, Ca2 + and K+ channels in neuronal dendrites and their functions in EPSP integration and synaptic plasticity. In particular, the author focuses on the active dendrites of cerebellar Purkinje cells and hippocampal CA1 pyramidal cells.
2. Voltage-gated Na+ and Ca2 + channels at neuronal dendrites The dendrites of many types of neurons contain voltage-gated Na+ and Ca2 + channels (Usowicz et al., 1992; Magee and Johnston, 1995a,b) that can generate action potentials. In cerebellar Purkinje cells, Ca2 + spikes are generated locally in the dendritic regions and Na+ spikes are initiated in the axon and then spread passively into the dendritic tree (Llina´s and Sugimori, 1980a,b; Stuart and Hausser, 1994). Back-propagating Na+ spikes, that actively invade the dendrites from the axon initial segment, are generated in the dendritic regions of hippocampal CA1 pyramidal cells (Jaffe et al., 1992; Colbert and Johnston, 1996). The functions of these spikes are not yet well understood, but the Ca2 + entry that they evoke probably serves to modulate Ca2 + -activated processes in the neuronal dendrites.
2.1. Dendritic Na+ channels in hippocampal CA1 pyramidal cells Subthreshold synaptic inputs (EPSPs) to hippocampal CA1 pyramidal cells activate dendritic voltagegated Na+ and Ca2 + channels. EPSP-gated Na+ channels open when the EPSP is close to its peak value, whereas low voltage-gated Ca2 + channels in the same cells open both at the EPSP peak and during its decay phase (Magee and Johnston, 1995b). However, the activation of dendritic high voltage-gated Ca2 + channels requires back-propagated Na+ action potentials generated at the axon initial segment. In other words, Ca2 + entry into dendrites is triggered by back-propagating dendritic Na+ action potentials that actively
invade the dendrites from the cell soma (Jaffe et al., 1992). Generation of back-propagating dendritic action potentials is necessary for the induction of long-term potentiation (LTP) in CA1 cells (Magee and Johnston, 1997). Pairing of subthreshold EPSPs with back-propagating action potentials results in an amplification of dendritic action potentials and evokes strong Ca2 + influx near the site of the synaptic input (Magee and Johnston, 1997). Back-propagating Na+ action potentials may provide a synaptically controlled, associative signal to the dendrites that allows Hebbian modifications of synaptic strength in an input-specific manner.
2.2. Dendritic Ca 2 + channels in cerebellar Purkinje cells In cerebellar Purkinje cells, Ca2 + and Na+ spikes are produced locally in dendritic and somatic regions, respectively (Llina´s and Sugimori, 1980a,b; Stuart and Hausser, 1994). Purkinje cells receive excitatory synaptic inputs from two sources: climbing fiber (CF) and parallel fibers (PF). Both inputs generate dendritic Ca2 + spikes, which are summed together (Lev-Ram et al., 1992; Miyakawa et al., 1992). Long term depression (LTD) is known to be induced by associative PF and CF stimulation at Purkinje cells (Ito, 1984). PF-induced Ca2 + spikes were confined to a small part of the spiny dendrites (Eilers et al., 1995). The voltage-dependency and the latency of Ca2 + spike activation in Purkinje cell dendrites are strongly reduced by 4-aminopyridine (4-AP), (Midtgaard et al., 1993; Midtgaard, 1994). These results suggest that a transient 4-AP-sensitive A-like current regulates the generation of Ca2 + spikes and the localization of Ca2 + influx in Purkinje cell dendrites. Dendritic K+ channels dynamically modulate the spatial integration, and influence the compartmentalization, of Ca2 + spikes and [Ca2 + ]i changes in the dendrites of Purkinje cells. Dendritic Ca2 + -spike generation is also regulated by low voltage-gated Ca2 + channels. Watanabe et al. (1998) studied the distribution and function of two types of voltage-gated Ca2 + channels in rat cerebellar Purkinje cells using simultaneous Ca2 + imaging and whole-cell patch clamp recording techniques. In this study, poor space clamp due to extensive arborization of the dendrites allowed the dendrites to fire Ca2 + spikes. Ca2 + imaging with fura-2 showed a depolarized pulse linked long-lasting [Ca2 + ]i increase at the soma and spike-linked [Ca2 + ]i jumps in the dendrites. v-Agatoxin-IVA (a P channel blocker) abolished the depolarization-induced Ca2 + spikes (that is, the spike-linked [Ca2 + ]i increase in the dendrites and the steady [Ca2 + ]i increase at the soma). A cocktail of v-Conotoxin-GVIA and nifedipine (blockers of N- and L- type Ca2 + channels) had no significant effects on the spike-linked [Ca2 + ]i increase. Low concentrations of NiCl2 reversibly suppressed this
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]i, coupled to Ca2 + spikes, has been suggested to play a crucial role in dendritic functions. Dendritic Ca2 + spike generation is regulated by many kinds of dendritic voltage-gated channels (e.g. K+ channels, low voltage-gated Ca2 + channels). The modulatory mechanisms of action potentials at neuronal dendrites may be essential for many aspects of dendritic function.
3. Roles of K+ channels in EPSP integration at neuronal dendrites
Fig. 1. Onset of the depolarization-induced dendritic Ca2 + spike in Purkinje cells revealed by a T-like Ca2 + channel blocker (NiCl2). A depolarizing voltage command pulse ( +70 mV) evoked a dendritic Ca2 + spike under the voltage clamp conditions (holding potential: −90 mV). NiCl2 (100 mM) slowed the onset of the Ca2 + spike without changing the time course of the spikes. (A, Control condition; B, in the presence of 100 mM NiCl2). (Modified from Watanabe et al., 1998).
[Ca2 + ]i increase. Low concentrations of NiCl2 slowed the onset of the Ca2 + spike without changing the time course of the spikes (Fig. 1) or the amplitude of the accompanying [Ca2 + ]i increase. These results suggest that v-Agatoxin-IVA-sensitive Ca2 + channels (P channels) are distributed both in the soma and the dendrites, and are responsible for dendritic Ca2 + spikes, whereas low voltage-gated, Ni2 + -sensitive Ca2 + channels (Tlike channels?) are distributed throughout the dendrites, including both thick and fine branches, and provide boosting currents for spike generation (which, as mentioned above, may be important in synaptic plasticity, e.g. LTP and LTD). Local increases in dendritic [Ca2 +
In contrast to Na+ and Ca2 + channels, voltagegated K+ channels cannot produce action potentials on their own. Voltage-gated K+ channels maintain the resting potential and regulate the repolarization of action potentials. Voltage-gated K+ channels are also considered to participate actively in temporal integration (Storm, 1988). Many kinds of voltage-gated K+ channels have been found in neuronal dendrites (Rudy, 1988). Recently, the physiological and pharmacological profiles of dendritic K+ channels have been determined in Purkinje cells (Housegard and Mitdgard, 1988) and hippocampal pyramidal cells (Hoffman et al., 1997). CA1 pyramidal cells possess many different kinds of the K+ channels (Storm, 1990). In particular, A-type K+ (KA) channels and/or D-type K+ (KD) channels have been proposed to play important roles in EPSP integration (Storm, 1987, 1990; Hoffman et al., 1997). More recently, the physiological functions of KA channels in EPSP integration has become clear (Debanne et al., 1997; Hoffman et al., 1997), while the physiological functions of KD channels in EPSP integration are not yet understood. Furthermore, the way in which these channels were together during EPSP integration is completely unknown. Using a computer simulation program (NEURON; Hines, 1993) instead of conventional electrophysiological methods, Takagi et al. (1998) suggested that KD channels can play a major role in EPSP integration in dendrites by altering their cable proper-
Fig. 2. Computer-simulated effects of KA and KD channels on a single EPSP. An EPSP was induced by a single synaptic input and recorded both at the input site (upper trace) and at another site 600 mm away (lower trace). Passive, containing no channels; KA, containing KA channels; KD, containing KD channels; KA and KD, containing both KA and KD channels (Takagi et al., 1998).
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ties (Fig. 2). KA channels have been experimentally demonstrated to be active mainly during LTP expression (Hoffman et al., 1997). KD channels are also suggested to be involved in LTP expression (Hoffman and Johnston, 1998). The physiological roles of dendritic KA and KD channels during LTP induction are still unknown. According to information theory, self-information in a continuous event is meaningless, because self-information cannot be expresses by integration (Gallager, 1968). Furthermore, pairing of subthreshold EPSPs with back-propagating action potentials is needed for LTP induction as mentioned above (Magee and Johnston, 1997). Therefore, each of sequential synaptic inputs has its own information independently and should be equally transmitted to the cell soma from the input-site during the high-frequency synaptic inputs. Takagi et al. (unpublished data) have also shown that the physiological roles of KA and KD channels during sequential synaptic inputs is to stabilize dendritic synaptic information for LTP induction. These K+ channels make co-operative contributions to EPSP reduction during high-frequency synaptic inputs. The existence of KA and KD channels may be necessary to reduce EPSP strength steadily during the high-frequency synaptic inputs require for LTP induction. Analyses of dendritic ion channels using computer simulations, together with an understanding of information theory, will help to clarify the co-operative roles of the various kinds of voltage-gated ion channels in dendritic function.
4. Conclusions The conventional view of EPSP integration is as a simple summation of the electrical signals produced by each active synapse innervating a given neuron. Because synaptic action can produce the postsynaptic electrical signals and the intracellular biochemical events such as the generation of second messengers, EPSP integration at neuronal dendrites can be modulated by ion currents and/or second messengers. We are now considering this possibility by examining changes in the concentration of dendrite, calcium resulting from subthreshold excitatory synaptic activity in, for example, cerebellar Purkinje cells. The author has described here several lines of evidence suggesting that EPSP integration occurs as a result of both electrical and non-electrical signals in restricted dendritic compartments composed of spines and their adjacent fine dendrites. Combined experimental and computational approaches have helped to clarify the biophysical behaviors of dendritic ion channels such as Ca2 + -gated K+ channels (Sah and Bekkers, 1996) as well as Na+ and Ca2 + channels (Warman et al., 1994). Likewise, the author believes that analyses of dendritic ion chan-
nels using combined experimental and theoretical approaches can open the door to a new wave of discoveries about EPSP integration.
Acknowledgements I thank Professor Hideo Suzuki (Waseda University), Dr Etsuro Ito (Hokkaido University) and Dr Timo Hannay (Nature Japan K.K.) for their critical reading of the manuscript. This work was partly supported by Grants-in-aid (Nos. 0878077 and 09780741) from the Ministry of Education, Science, Sports and Culture of Japan, and the grants from the Inamori Foundation and the Narishige Foundation to H. Takagi.
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Update Article
Roles of ion channels in EPSP integration at neuronal dendrites Hiroshi Takagi * Department of Neuroplasticity, Research Center for Aging and Adaptation, Shinshu Uni6ersity School of Medicine, Matsumoto, Nagano 390 -8621, Japan Received 23 February 2000; accepted 23 March 2000
Abstract Many different kinds of voltage-gated ion channels (Na+ channels, K+ channels, Ca2 + channels) exist at neuronal dendrites. Integration of dendritic electric signals (excitatory postsynaptic potentials (EPSPs), inhibitory postsynaptic potentials (IPSPs) and action potentials) and/or non-electric signals (Ca2 + and second messengers) occurs in restricted dendritic compartments consisting of spines and adjacent fine dendrites. Voltage-gated ion channels at neuronal dendrites play crucial roles in the integration of dendritic signals. Dendritic signals, in turn, play important roles in the modulation of local dendritic physiological functions (e.g. input-specific synaptic plasticity, long-term potentiation (LTP) and long term depression (LTD)). A combined experimental and theoretical approach is a good way to clarify the biophysical behaviors of dendritic ion channels. Analyses of dendritic ion channels can open the door to a new wave of discoveries about EPSP integration at neuronal dendrites. © 2000 Elsevier Science Ireland Ltd and the Japan Neuroscience Society. All rights reserved. Keywords: Dendritic integration; Na+ channels; Ca2 + channels; K+ channels; Computer simulation; Cable theory
1. Introduction A central aspect of neuronal function is to translate synaptic inputs into a sequence of action potentials that carry information along the axon, coded temporarily and/or coded as spike frequency. Cable filtering of the synaptic currents reduces the amplitude of excitatory and/or inhibitory postsynaptic potentials (EPSPs and/ or IPSPs) and limits spatial summation among distributed synapses (so-called dendritic integration), strongly regulating the impact of many synapses on neuronal outputs (Jaslove, 1992; Spruston et al., 1993, 1994). For most of the 20th century, neuronal dendrites were considered to be passive cables satisfying cable equations (Rall, 1997). This view was challenged in the 1960s by reports of dendritic action potentials in cerebral pyramidal cells (Spencer and Kandel, 1961) and cerebellar Purkinje cells (Llina´s et al., 1968). Recently, many kinds of neuronal dendrites, such as hippocampal * Tel.: +81-263-372728; fax: + 81-263-372725. E-mail address: [email protected] (H. Takagi).
pyramidal cells and cerebral cortical pyramidal cells, have been confirmed to be ‘active’ cables that do not necessarily satisfy passive cable theory. Neuronal dendrites contain a variety of voltage-gated ion channels that enable action potentials and EPSPs to propagate actively throughout the neuron (Johnston et al., 1996; Yuste and Tank, 1996). For example, voltage-gated Ca2 + channels are mainly expressed in the dendritic regions of cerebellar Purkinje cells, while voltage-gated Na+ channels are widely expressed in the dendritic regions of cerebral cortical pyramidal cells (Llina´s and Sugimori, 1980b; Stuart and Sakmann, 1994). Activation of these dendritic voltage-gated ion channels, following the integration of many synaptic inputs (EPSP integration), produces plateau and spiky local potentials in the dendritic regions. These local potentials induce a rise in local intracellular Ca2 + concentration ([Ca2 + ]i), which modulates Ca2 + -activated ion channels and drives Ca2 + -activated signal transduction systems. Because synaptic activation can induce the production of postsynaptic electrical signals and intracellular biochemical events such as the generation of
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second messengers, EPSP integration may be affected by second messengers (Bourne and Nicoll, 1993). One of the most remarkable findings of recent years is the demonstration of highly localized Ca2 + transients that are limited to small dendritic segments and even to single dendritic spines (Eilers and Konnerth, 1997). In addition, by use of a two-photon excitation imaging technique it has been possible to reveal the existence of dendritic Ca2 + signals even in the neocortical pyramidal cells of anaesthetized rats (Svoboda et al., 1997). These local physiological changes may induce local dendritic functional modulations, such as input-specific synaptic plasticity (Alger and Teyler, 1976; Andersen et al., 1977). This article describes recent data regarding the various types of voltage-gated Na+, Ca2 + and K+ channels in neuronal dendrites and their functions in EPSP integration and synaptic plasticity. In particular, the author focuses on the active dendrites of cerebellar Purkinje cells and hippocampal CA1 pyramidal cells.
2. Voltage-gated Na+ and Ca2 + channels at neuronal dendrites The dendrites of many types of neurons contain voltage-gated Na+ and Ca2 + channels (Usowicz et al., 1992; Magee and Johnston, 1995a,b) that can generate action potentials. In cerebellar Purkinje cells, Ca2 + spikes are generated locally in the dendritic regions and Na+ spikes are initiated in the axon and then spread passively into the dendritic tree (Llina´s and Sugimori, 1980a,b; Stuart and Hausser, 1994). Back-propagating Na+ spikes, that actively invade the dendrites from the axon initial segment, are generated in the dendritic regions of hippocampal CA1 pyramidal cells (Jaffe et al., 1992; Colbert and Johnston, 1996). The functions of these spikes are not yet well understood, but the Ca2 + entry that they evoke probably serves to modulate Ca2 + -activated processes in the neuronal dendrites.
2.1. Dendritic Na+ channels in hippocampal CA1 pyramidal cells Subthreshold synaptic inputs (EPSPs) to hippocampal CA1 pyramidal cells activate dendritic voltagegated Na+ and Ca2 + channels. EPSP-gated Na+ channels open when the EPSP is close to its peak value, whereas low voltage-gated Ca2 + channels in the same cells open both at the EPSP peak and during its decay phase (Magee and Johnston, 1995b). However, the activation of dendritic high voltage-gated Ca2 + channels requires back-propagated Na+ action potentials generated at the axon initial segment. In other words, Ca2 + entry into dendrites is triggered by back-propagating dendritic Na+ action potentials that actively
invade the dendrites from the cell soma (Jaffe et al., 1992). Generation of back-propagating dendritic action potentials is necessary for the induction of long-term potentiation (LTP) in CA1 cells (Magee and Johnston, 1997). Pairing of subthreshold EPSPs with back-propagating action potentials results in an amplification of dendritic action potentials and evokes strong Ca2 + influx near the site of the synaptic input (Magee and Johnston, 1997). Back-propagating Na+ action potentials may provide a synaptically controlled, associative signal to the dendrites that allows Hebbian modifications of synaptic strength in an input-specific manner.
2.2. Dendritic Ca 2 + channels in cerebellar Purkinje cells In cerebellar Purkinje cells, Ca2 + and Na+ spikes are produced locally in dendritic and somatic regions, respectively (Llina´s and Sugimori, 1980a,b; Stuart and Hausser, 1994). Purkinje cells receive excitatory synaptic inputs from two sources: climbing fiber (CF) and parallel fibers (PF). Both inputs generate dendritic Ca2 + spikes, which are summed together (Lev-Ram et al., 1992; Miyakawa et al., 1992). Long term depression (LTD) is known to be induced by associative PF and CF stimulation at Purkinje cells (Ito, 1984). PF-induced Ca2 + spikes were confined to a small part of the spiny dendrites (Eilers et al., 1995). The voltage-dependency and the latency of Ca2 + spike activation in Purkinje cell dendrites are strongly reduced by 4-aminopyridine (4-AP), (Midtgaard et al., 1993; Midtgaard, 1994). These results suggest that a transient 4-AP-sensitive A-like current regulates the generation of Ca2 + spikes and the localization of Ca2 + influx in Purkinje cell dendrites. Dendritic K+ channels dynamically modulate the spatial integration, and influence the compartmentalization, of Ca2 + spikes and [Ca2 + ]i changes in the dendrites of Purkinje cells. Dendritic Ca2 + -spike generation is also regulated by low voltage-gated Ca2 + channels. Watanabe et al. (1998) studied the distribution and function of two types of voltage-gated Ca2 + channels in rat cerebellar Purkinje cells using simultaneous Ca2 + imaging and whole-cell patch clamp recording techniques. In this study, poor space clamp due to extensive arborization of the dendrites allowed the dendrites to fire Ca2 + spikes. Ca2 + imaging with fura-2 showed a depolarized pulse linked long-lasting [Ca2 + ]i increase at the soma and spike-linked [Ca2 + ]i jumps in the dendrites. v-Agatoxin-IVA (a P channel blocker) abolished the depolarization-induced Ca2 + spikes (that is, the spike-linked [Ca2 + ]i increase in the dendrites and the steady [Ca2 + ]i increase at the soma). A cocktail of v-Conotoxin-GVIA and nifedipine (blockers of N- and L- type Ca2 + channels) had no significant effects on the spike-linked [Ca2 + ]i increase. Low concentrations of NiCl2 reversibly suppressed this
H. Takagi / Neuroscience Research 37 (2000) 167–171
169
]i, coupled to Ca2 + spikes, has been suggested to play a crucial role in dendritic functions. Dendritic Ca2 + spike generation is regulated by many kinds of dendritic voltage-gated channels (e.g. K+ channels, low voltage-gated Ca2 + channels). The modulatory mechanisms of action potentials at neuronal dendrites may be essential for many aspects of dendritic function.
3. Roles of K+ channels in EPSP integration at neuronal dendrites
Fig. 1. Onset of the depolarization-induced dendritic Ca2 + spike in Purkinje cells revealed by a T-like Ca2 + channel blocker (NiCl2). A depolarizing voltage command pulse ( +70 mV) evoked a dendritic Ca2 + spike under the voltage clamp conditions (holding potential: −90 mV). NiCl2 (100 mM) slowed the onset of the Ca2 + spike without changing the time course of the spikes. (A, Control condition; B, in the presence of 100 mM NiCl2). (Modified from Watanabe et al., 1998).
[Ca2 + ]i increase. Low concentrations of NiCl2 slowed the onset of the Ca2 + spike without changing the time course of the spikes (Fig. 1) or the amplitude of the accompanying [Ca2 + ]i increase. These results suggest that v-Agatoxin-IVA-sensitive Ca2 + channels (P channels) are distributed both in the soma and the dendrites, and are responsible for dendritic Ca2 + spikes, whereas low voltage-gated, Ni2 + -sensitive Ca2 + channels (Tlike channels?) are distributed throughout the dendrites, including both thick and fine branches, and provide boosting currents for spike generation (which, as mentioned above, may be important in synaptic plasticity, e.g. LTP and LTD). Local increases in dendritic [Ca2 +
In contrast to Na+ and Ca2 + channels, voltagegated K+ channels cannot produce action potentials on their own. Voltage-gated K+ channels maintain the resting potential and regulate the repolarization of action potentials. Voltage-gated K+ channels are also considered to participate actively in temporal integration (Storm, 1988). Many kinds of voltage-gated K+ channels have been found in neuronal dendrites (Rudy, 1988). Recently, the physiological and pharmacological profiles of dendritic K+ channels have been determined in Purkinje cells (Housegard and Mitdgard, 1988) and hippocampal pyramidal cells (Hoffman et al., 1997). CA1 pyramidal cells possess many different kinds of the K+ channels (Storm, 1990). In particular, A-type K+ (KA) channels and/or D-type K+ (KD) channels have been proposed to play important roles in EPSP integration (Storm, 1987, 1990; Hoffman et al., 1997). More recently, the physiological functions of KA channels in EPSP integration has become clear (Debanne et al., 1997; Hoffman et al., 1997), while the physiological functions of KD channels in EPSP integration are not yet understood. Furthermore, the way in which these channels were together during EPSP integration is completely unknown. Using a computer simulation program (NEURON; Hines, 1993) instead of conventional electrophysiological methods, Takagi et al. (1998) suggested that KD channels can play a major role in EPSP integration in dendrites by altering their cable proper-
Fig. 2. Computer-simulated effects of KA and KD channels on a single EPSP. An EPSP was induced by a single synaptic input and recorded both at the input site (upper trace) and at another site 600 mm away (lower trace). Passive, containing no channels; KA, containing KA channels; KD, containing KD channels; KA and KD, containing both KA and KD channels (Takagi et al., 1998).
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ties (Fig. 2). KA channels have been experimentally demonstrated to be active mainly during LTP expression (Hoffman et al., 1997). KD channels are also suggested to be involved in LTP expression (Hoffman and Johnston, 1998). The physiological roles of dendritic KA and KD channels during LTP induction are still unknown. According to information theory, self-information in a continuous event is meaningless, because self-information cannot be expresses by integration (Gallager, 1968). Furthermore, pairing of subthreshold EPSPs with back-propagating action potentials is needed for LTP induction as mentioned above (Magee and Johnston, 1997). Therefore, each of sequential synaptic inputs has its own information independently and should be equally transmitted to the cell soma from the input-site during the high-frequency synaptic inputs. Takagi et al. (unpublished data) have also shown that the physiological roles of KA and KD channels during sequential synaptic inputs is to stabilize dendritic synaptic information for LTP induction. These K+ channels make co-operative contributions to EPSP reduction during high-frequency synaptic inputs. The existence of KA and KD channels may be necessary to reduce EPSP strength steadily during the high-frequency synaptic inputs require for LTP induction. Analyses of dendritic ion channels using computer simulations, together with an understanding of information theory, will help to clarify the co-operative roles of the various kinds of voltage-gated ion channels in dendritic function.
4. Conclusions The conventional view of EPSP integration is as a simple summation of the electrical signals produced by each active synapse innervating a given neuron. Because synaptic action can produce the postsynaptic electrical signals and the intracellular biochemical events such as the generation of second messengers, EPSP integration at neuronal dendrites can be modulated by ion currents and/or second messengers. We are now considering this possibility by examining changes in the concentration of dendrite, calcium resulting from subthreshold excitatory synaptic activity in, for example, cerebellar Purkinje cells. The author has described here several lines of evidence suggesting that EPSP integration occurs as a result of both electrical and non-electrical signals in restricted dendritic compartments composed of spines and their adjacent fine dendrites. Combined experimental and computational approaches have helped to clarify the biophysical behaviors of dendritic ion channels such as Ca2 + -gated K+ channels (Sah and Bekkers, 1996) as well as Na+ and Ca2 + channels (Warman et al., 1994). Likewise, the author believes that analyses of dendritic ion chan-
nels using combined experimental and theoretical approaches can open the door to a new wave of discoveries about EPSP integration.
Acknowledgements I thank Professor Hideo Suzuki (Waseda University), Dr Etsuro Ito (Hokkaido University) and Dr Timo Hannay (Nature Japan K.K.) for their critical reading of the manuscript. This work was partly supported by Grants-in-aid (Nos. 0878077 and 09780741) from the Ministry of Education, Science, Sports and Culture of Japan, and the grants from the Inamori Foundation and the Narishige Foundation to H. Takagi.
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