The ‘window’ T-type calcium current in brain dynamics of different behavioural states
1 School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3US, UK
Abstract
All three forms of recombinant low voltage-activated T-type Ca2+ channels (Cav3.1, Cav3.2 and Cav3.3) exhibit a small, though clearly evident, window T-type Ca2+ current (ITwindow) which is also present in native channels from different neuronal types. In thalamocortical (TC) and nucleus reticularis thalami (NRT) neurones, and possibly in neocortical cells, an ITwindow-mediated bistability is the key cellular mechanism underlying the expression of the slow (< 1 Hz) sleep oscillation, one of the fundamental EEG rhythms of non-REM sleep. As the ITwindow-mediated bistability may also represent one of the cellular mechanisms underlying the expression of high frequency burst firing in awake conditions, ITwindow is of critical importance in neuronal population dynamics associated with different behavioural states.
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Introduction
Low voltage-activated T-type Ca2+ channels are an important component of the large array of voltage-dependent membrane channels used by neurones to express different network dynamics. Their characteristic voltage dependence and kinetics allow them to generate a transient, depolarizing, low-threshold Ca2+ spike or potential (LTCP) which in turn evokes a peculiar firing pattern consisting of a high frequency (100–400 Hz) burst of action potentials (Huguenard, 1996; Perez-Reyes, 2003). Since the work of Llinas's group in Purkinje (Llinas & Sugimori, 1980a,b) and inferior olive neurones (Llinas & Yarom, 1981a,b), the physiological expression of neuronal T-type Ca2+ channels has now been demonstrated in different neurones and has become synonymous with LTCP generation and burst firing.
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Recent work in thalamic neurones indicates that neuronal T-type Ca2+ channels also underlie membrane potential bistability, i.e. the existence of two resting membrane potentials. This neuronal property is due to the window current generated by these channels, i.e. ITwindow (Williams et al. 1997; Toth et al. 1998). Here, we summarize the biophysics underlying the physiological expression of ITwindow, and describe how the ITwindow-mediated bistability in thalamic neurones is a key component in the generation of the slow (< 1 Hz) sleep rhythm (Hughes et al. 2002), one of the fundamental EEG activities in non-REM sleep dynamics (Steriade et al. 1993d). In a prospective outlook we will then consider how neuronal ITwindow may underlie other activities during the awake state. The distinct and important physiological roles that ITwindow plays in non-neuronal cells have been reviewed elsewhere (Lambert et al. 2001; Perez-Reyes, 2003).
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Biophysics of ITwindow
The window (or steady-state) component of an inactivating, voltage-dependent membrane current originates from the region of overlap (shaded in grey in Fig. 1Aa) between its steady-state activation and inactivation curves. In this voltage region, there is a fraction of channels which do not fully inactivate and therefore remain open. The estimated magnitude of the window current is strongly dependent on the steepness of these curves and their relative position with respect to the voltage axis (Fig. 1Aa). Since the activation and inactivation curves are obtained by fitting exponential functions to experimental measurements that in this voltage region are very small and highly dependent on the experimental conditions, great caution should be used in interpreting data on window currents. Furthermore, because these curves decay exponentially towards the voltage axis (i.e. they tend to zero at infinity) (Fig. 1Aa), all inactivating currents, including those with steady-state activation and inactivation curves that are far apart and shallow, possess a window current, even if extremely small. As has been the case for other inactivating currents, therefore, the issue is not whether neuronal ITwindow exists, but rather whether it has any physiological role, i.e. whether the small fraction of ‘non-inactivating’ neuronal T-type Ca2+ channels responsible for ITwindow makes any contribution to single neurone activities and neural network dynamics.
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Aa, steady-state activation and inactivation curves of IT from a TC neurone in vitro, showing in grey the region of overlap, i.e. the basis for ITwindow. b, plot of the absolute value of ITwindow (bell-shaped curve) and two Ileaks (blue and green lines). c, net current–voltage plot for the colour coded conditions depicted in b: bistability, i.e. two stable membrane potentials (filled and open circle), is present for the green but not for the blue line. d, plot of the small Ileak as in b and a small ITwindow (red curve) shows only one point of intersection. e, plot of the small Ileak and ITwindow as in d, but with two steady inward currents (continuous and dashed purple lines). f, net current–voltage plot for the colour coded conditions depicted in d and e: bistability is absent when IT is small (red line), but can be reintroduced by addition of a steady inward current that shifts the curve downwards (continuous purple line). A larger inward current further shifts the curve downwards with a loss of bistability and an instatement of a more depolarized membrane potential (open circle on dashed purple line). B, steady-state activation and inactivation curves for recombinant Cav3.1, Cav3.2 and Cav3.3 channels (a), and corresponding window currents (b). C, bistability is observed in TC neurones when Ih is blocked with ZD 7288. The transition from one to the other resting potential is achived by intracellular injection of current pulses. Da, following the block of IT with Ni2+, bistability is reintroduced in this TC neurone by using an amount of computer-generated IT commensurate with the theoretical prediction (i.e. the unfilled and filled circles of the green line in the voltage-net current plot match the two experimentally measured resting membrane potentials). A decrease in artificial gT to 140 nS (bottom records) abolishes the bistability as the voltage–net current plot now has only one resting membrane potential (filled circle of red line), as shown in Ab and Ad. However, using the same gT, bistability is reintroduced by the addition of a steady direct current (continuous purple line), as shown in Ae and Af. B used from Perez-Reyes, (2003) with permission ( 2003, American Physiological Society).
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A small, but clearly discernable, ITwindow was evident in the first studies that investigated native neuronal T-type Ca2+ channels (Carbone & Lux, 1984; Nowycky et al. 1985; Fox et al. 1987). Since then, ITwindow has been observed in many neuronal types (including the thalamic neurones on which this review will focus) (Coulter et al. 1989; Crunelli et al. 1989; Hernandez-Cruz & Pape, 1989) (Fig. 1Aa), using different preparations and techniques in both young and adult animals of different species (Huguenard, 1996; Perez-Reyes, 2003). From these data, ITwindow may be estimated to be generated by 0.05–0.8% of the total number of T-type channels in different CNS neurones. Recent investigations on recombinant Cav3.1, Cav3.2 and Cav3.3 channels (derived from the respective 1G, 1H and 1I pore forming subunits) have confirmed the results on native channels (Fig. 1Ba), and highlighted a larger ITwindow for Cav3.3 channels than for the other two types (Klockner et al. 1999) (Fig. 1Bb). These data are particularly important for thalamic cells, since glutamatergic thalamocortical (TC) neurones mostly express Cav3.1 and a very small number of Cav3.2 channels, whereas the GABAergic neurones of the nucleus reticularis thalami (NRT) are mainly endowed with Cav3.3 and much smaller amounts of Cav3.1 and Cav3.2 channels (Talley et al. 1999; Perez-Reyes, 2003).
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Neuronal ITwindow and membrane potential bistability
The transient activation of neuronal T-type Ca2+ channels generates the characteristic LTCP and associated high frequency burst firing. In contrast, the non-inactivating fraction of T-type Ca2+ channels leads, in the generally small membrane potential region of their expression, to a ‘steady’ influx of Ca2+ into the neurone, and thus to a ‘non-inactivating’ inward current (ITwindow) and a resulting ‘tonic’ depolarization. To fully appreciate the physiological significance of ITwindow in neuronal activity, however, it is necessary to consider the interaction between this current and the leak K+ current (Ileak) in the absence of other membrane currents. In Fig. 1Ab, the absolute amplitude of ITwindow (bell-shaped curve) has been plotted against the membrane potential, while two Ileaks are represented by the blue and green lines. When the slope of Ileak (i.e. gleak) is relatively small (green line in Fig. 1Ab), Ileak crosses the bell-shaped ITwindow curve in three points, at which both currents have equal values. Since ITwindow is an inward and Ileak an outward current, these are three points of zero net current (Fig. 1Ac): the leftmost and rightmost points are stable equilibrium points (filled and open circles on green line in Fig. 1Ac, respectively) whilst the middle point is unstable (i.e. grey circle in Fig. 1Ac). Under this condition the system generated by ITwindow and Ileak is bistable and, in the absence of other currents in this voltage region, neurones show two stable resting membrane potentials: one depolarized state where ITwindow is ‘on’ (open circle on green line in Fig. 1Ac) and a hyperpolarized state where ITwindow is ‘off’ (filled circle on green line in Fig. 1Ac). In contrast, when gleak is relatively large (blue line in Fig. 1Ab) Ileak crosses the ITwindow curve only in one point, which represents the resting membrane potential (filled circle on blue line in Fig. 1Ac).
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Clearly, changes in Ileak are not the only modifications that can bring about or remove ITwindow-mediated bistability. As shown in Fig. 1Ad, bistability is lost when a small Ileak interacts with a small ITwindow, which may result either from a reduction in gT, rightward and leftward shifts in its steady-state activation and inactivation curve, respectively, or a decrease in their steepness. This would give rise to a single equilibrium point (filled circle on red line in Fig. 1Af). Also important, both from a biophysical and physiological perspective, are the cases where in the absence of any change in both ITwindow and Ileak, bistability can be instated or eliminated by addition of a tonic current (Fig. 1Ae). For example, in the non-bistable system of Fig. 1Ad, addition of a steady inward current (continuous purple line in Fig. 1Ae) would shift the entire net current–voltage curve downwards (continuous purple line in Fig. 1Af), thus reintroducing bistability. Addition of a larger steady inward current (dashed purple line in Fig. 1Ae) would then remove bistability, moving the curve even further downwards and thus allowing only one resting membrane potential to exist (open circle on dashed purple line in Fig. 1Af).
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Physiological expression of ITwindow
Experimental confirmation of the presence of a physiologically relevant ITwindow has come from work in rat and cat TC neurones (Williams et al. 1997; Hughes et al. 1999; Hughes et al. 2002), of different sensory and motor thalamic nuclei (Blethyn et al. 2002), and NRT neurones (Blethyn et al. 2003). In these neurones bistability is observed after appropriate block of Ih (the most prominent current present within the voltage region where ITwindow is expressed), and, as predicted, appropriate voltage steps are able to switch the membrane potential between the two stable states (Williams et al. 1997) (Fig. 1C). This bistability is unaffected by Ba2+ and blockers of high threshold Ca2+ currents, including Cd2+, but is abolished by relatively small concentrations of Ni2+ (see Fig. 2D). The preferential block by Ni2+, compared to the lack of effect by similar concentrations of Cd2+, indicates that bistability is dependent on IT.
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A, bistability in computer simulations using a TC neurone model containing only IT and Ileak (upper trace). Note the similarity of the waveform to the experimental records in Fig. 1C. Addition of Ih leads to a continuous oscillation of the membrane potential (middle trace), the period of which is drastically affected by the further addition of ICAN to the model (lower trace). B, similarities of the slow (< 1 Hz) sleep oscillation observed in vitro and in vivo (the latter recorded simultaneously with the slow (< 1 Hz) rhythm in the EEG. C, in every TC neurone in vitro, the non-selective mGluR agonist (+/–)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) elicits the slow (< 1 Hz) sleep oscillation, which is unaffected by the selective mGluR5 antagonist 2-methyl-G-(phenylethynyl) pyridine (MPEP), but blocked by the selective mGluR1a antagonist LY367385. D, block of the slow (< 1 Hz) sleep oscillation by Ni2+ but not by Cd2+. Downward deflections in the lowermost record are the neurone response to hyperpolarizing current pulses. E, the slow (< 1Hz) sleep oscillation recorded in an NRT neurone in vitro. B from contreras & Steriade (1995) with permission ( 1995 by the Society for Neuroscience). C and D from Sherman et al. (2001) with permission ( 2002, Elsevier).
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Additional and conclusive evidence for the involvement of ITwindow in the membrane potential bistability of thalamic neurones is provided by appropriately manipulating IT (and thus ITwindow) using the dynamic clamp (Hughes et al. 1999, 2002), a technique that allows a computer-generated current to be either added to, or subtracted from a living neurone (Sharp et al. 1993). Thus, in an originally bistable TC neurone where IT (and thus bistability) had been pharmacologically eliminated by Ni2+, bistability can be reinstated by adding an amount of computer-generated IT commensurate with the apparent Ileak of that neurone, such that the net current–voltage plot for that neurone satisfies the theoretical prediction (green line in Fig. 1Da). Similar dynamic clamp experiments (Hughes et al. 1999) also demonstrate that TC neurones lose their bistable properties by changes in artificial IT that decrease the size of ITwindow, for instance by moving apart the steady-state activation and inactivation curves of the computer generated IT by as little as 5 mV, or by reducing gT (red line in Fig. 1Da, see also Fig. 1Ad and Af). In the latter case, bistability could then be re-introduced by an appropriate change in direct current (continuous purple line in Fig. 1Ab), as explained in the previous section (see Fig. 1Ae and Af).
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ITwindow-mediated bistability is the cellular mechanism of the slow sleep ( 1 Hz) oscillation
As shown by computer simulations, addition of the hyperpolarization-activated current (Ih) drastically transforms the ITwindow–Ileak bistable system into a continuous oscillation of the membrane potential (Fig. 2A), by introducing a voltage-dependent, non-inactivating inward current. The period, and other properties of this oscillation, are also critically controlled by the presence of a Ca2+-dependent, non-selective cation current (ICAN) (Hughes et al. 2002) (Fig. 2A).
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This ITwindow-mediated, membrane potential oscillation is indeed the activity that is observed in TC and NRT neurones when Ih is not blocked (Fig. 2B). Extensive in vitro and in vivo studies (Hughes et al. 2002, 2004) have now shown it to represent the slow (< 1 Hz) sleep oscillation, i.e. the intracellularly recorded thalamic counterpart of the slow (< 1 Hz) sleep rhythm recorded in the EEG (Steriade et al. 1993a; Contreras & Steriade, 1995) (Fig. 2B). Both in animals (Steriade et al. 1993b) and in humans (Achermann & Borbely, 1997), this rhythm is one of the fundamental components of sleep dynamics during non-REM sleep, and a single slow (< 1 Hz) sleep oscillation cycle within the thalamocortical loop is now believed to underlie the expression of a K-complex in the EEG (Amzica & Steriade, 1997).
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The bistability, and the slow (< 1 Hz) sleep oscillation, however, can be seen in vitro only in a very small proportion (15%) of TC neurones under control conditions (Williams et al. 1997), but in 56% of TC neurones following electrical stimulation of the cortical afferents present in the slice (Hughes et al. 2002). Similarly, none of the TC neurones in vivo expresses the slow (< 1 Hz) oscillation following removal of the cortex (a condition similar to the in vitro situation), but the majority shows it when the cortex is left intact (Timofeev & Steriade, 1996). Together these in vitro and in vivo results show that the corticofugal afferents to TC neurones strongly contribute to setting the ITwindow–Ileak system to become bistable, either by changing Ileak or ITwindow, or adding/removing a tonic input (as shown schematically in Fig. 1Ab, d and e, respectively). In TC neurones that are non-oscillating in control conditions in vitro, the simple addition of direct current does not bring about the slow (< 1 Hz) sleep oscillation, and an increase in gT or a modification of its voltage region of expression (by manipulating the relative position of the steady-state activation and inactivation curves of computer-generated IT) does not satisfactorily reproduce all the properties of the slow (< 1 Hz) oscillation (Hughes et al. 1999). On the other hand, dynamic clamp experiments that decrease Ileak show an oscillation with identical characteristics to the one observed in vivo (Hughes et al. 1999). Indeed, it is the synaptic activation of metabotropic glutamate receptors (mGluR1a) that instates the decrease in Ileak necessary for establishing the ITwindow–Ileak bistable system, as also demonstrated in vivo and in vitro using selective mGluR agonists and antagonists (Hughes et al. 2002, 2004) (Fig. 2C).
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Figure 3 summarizes the cellular mechanism of the slow (< 1 Hz) sleep oscillation in TC neurones, where (i) ITwindow plays the major role by setting the level of the up (ITwindow ‘on’) and down (ITwindow ‘off’) states of the oscillation, (ii) Ih is responsible for repolarizing the neurone from the down state and thus critically determines the duration of the down state, and (iii) ICAN tightly controls the duration of the up state and is thus responsible for stabilizing the voltage region of existence of the slow oscillation (see Fig. 8 in Hughes et al. 2002). A very similar mechanism underlies the slow (< 1 Hz) sleep oscillation in NRT neurones (Fig. 2E), with ITwindow setting the basic levels for its up and down states (Blethyn et al. 2003).
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ITwindow-mediated bistability as a potential cellular mechanism of the high frequency bursts in the awake state
In the awake state, TC neurones are considerably more depolarized than during sleep, a situation similar to that depicted by the dashed purple line in Fig. 1Af where only one membrane potential exists (open circle) and bistability is not present. Computer simulations and in vitro experiments, however, have shown that even when the membrane potential of TC neurones is > –60 mV, a small EPSP (or IPSP) can temporarily bring the membrane potential into the voltage region where the ITwindow-mediated bistable mechanism could become transiently operational. This results in a stereotypical response consisting of a hyperpolarization (i.e. switching off of ITwindow) that is always terminated by an LTCP and associated high frequency burst firing (Fig. 4A and B), thus amplifying the output of TC neurones to small-amplitude, isolated, subthreshold synaptic potentials (Williams et al. 1997).
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A, computer simulations showing how at –60 mV two small EPSPs can evoke the stereotypical ITwindow-mediated response, consisting of a large hyperpolarization followed by an LTCP and high frequency firing. B, the same sequence of events as in A can be recorded in vitro in TC neurones. C, extracellular activity from a TC neurone of an awake behaving monkey showing high frequency bursts with putative characteristics of an LTCP-mediated event. C from Sherman (2001) with permission ( 2001, Elsevier).
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High frequency bursts have been shown to occur sporadically in some TC neurones of awake rats (Fanselow et al. 2001), guinea pigs (Massaux & Edeline, 2003), rabbits (Swadlow & Gusev, 2001), cats (Guido & Weyand, 1995) and monkeys (Ramcharan et al. 2000) (Fig. 4C), and often as part of the initial, though delayed, response to a sensory stimulus (Sherman, 2001). Although these bursts have been suggested to arise from the activation of T-type Ca2+ channels, no mechanism has been put forward to explain how this can occur from the relatively depolarized membrane potential that TC neurones occupy in the awake state. The ITwindow-mediated amplification described above might be one such explanation. In this scenario, the delay and the strength of the LTCP-mediated action potential burst would not be strictly set, but could be finely tuned by (i) the neurone's Ileak, which takes into account the overall background synaptic activity (Destexhe et al. 2001), (ii) the strength of Ih, which is known to be modulated by many thalamic transmitters (McCormick, 1992), and (iii) the number of T-type Ca2+ channels available for activation, which paradoxically is larger following a relatively prolonged period of depolarization (Leresche et al. 2004).
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Perspective outlook
The presence of Cav3.1, Cav3.2 and Cav3.3 channels in neurones of almost any brain region (Perez-Reyes, 2003) would support the notion that similar ITwindow-mediated activities as those described above for thalamic neurones may occur in various neuronal types throughout the brain. In particular, the ITwindow-mediated bistability might be the fundamental mechanism underlying the slow (< 1 Hz) sleep oscillation in neocortical cells (Steriade et al. 1993c), upon which synaptic influences would undoubtedly exert their modulation (Sanchez-Vives & McCormick, 2000).
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Although we have concentrated here on the electrical behaviours that occur as a result of the ITwindow-mediated bistability, one should not discard the potential presence of other physiologically relevant effects of ITwindow that are specifically linked to Ca2+ influx, for example the modulation of biochemical pathways and gene expression. With the known role of intracellular Ca2+ in short- and long-term neuronal plasticity, these actions could be of particular significance for thalamic and cortical neurones in view of recent data on the effect of the deep stages of non-REM sleep on memory (Huber et al. 2004).
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The discovery of a physiological role for ITwindow in thalamic neurones, and its likely involvement in the activities of many other neuronal types, clearly raise the question of potential alterations of this component of IT in neurological and psychiatric disorders. These could either be primary changes in IT that might contribute to pathophysiological conditions (Tsakiridou et al. 1995) or alterations in IT that are secondary to other abnormalities, such as extracellular pH changes (Shah et al. 2001), genetic mutations of other Ca2+ channels (Zhang et al. 2002), or continuous paroxysmal firing (Su et al. 2002).
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Footnotes
In memory of Eberhard H. Buhl. This report was presented at The Journal of Physiology Symposium in honour of the late Eberhard H. Buhl on Structure/Function Correlates in Neurons and Networks, Leeds, UK, 10 September 2004. It was commissioned by the Editorial Board and reflects the views of the authors.
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Zhang Y, Mori M, Burgess DL & Noebels JL (2002). Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. J Neurosci 22, 6362–6371., http://www.100md.com(Vincenzo Crunelli, Tibor )
Abstract
All three forms of recombinant low voltage-activated T-type Ca2+ channels (Cav3.1, Cav3.2 and Cav3.3) exhibit a small, though clearly evident, window T-type Ca2+ current (ITwindow) which is also present in native channels from different neuronal types. In thalamocortical (TC) and nucleus reticularis thalami (NRT) neurones, and possibly in neocortical cells, an ITwindow-mediated bistability is the key cellular mechanism underlying the expression of the slow (< 1 Hz) sleep oscillation, one of the fundamental EEG rhythms of non-REM sleep. As the ITwindow-mediated bistability may also represent one of the cellular mechanisms underlying the expression of high frequency burst firing in awake conditions, ITwindow is of critical importance in neuronal population dynamics associated with different behavioural states.
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Introduction
Low voltage-activated T-type Ca2+ channels are an important component of the large array of voltage-dependent membrane channels used by neurones to express different network dynamics. Their characteristic voltage dependence and kinetics allow them to generate a transient, depolarizing, low-threshold Ca2+ spike or potential (LTCP) which in turn evokes a peculiar firing pattern consisting of a high frequency (100–400 Hz) burst of action potentials (Huguenard, 1996; Perez-Reyes, 2003). Since the work of Llinas's group in Purkinje (Llinas & Sugimori, 1980a,b) and inferior olive neurones (Llinas & Yarom, 1981a,b), the physiological expression of neuronal T-type Ca2+ channels has now been demonstrated in different neurones and has become synonymous with LTCP generation and burst firing.
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Recent work in thalamic neurones indicates that neuronal T-type Ca2+ channels also underlie membrane potential bistability, i.e. the existence of two resting membrane potentials. This neuronal property is due to the window current generated by these channels, i.e. ITwindow (Williams et al. 1997; Toth et al. 1998). Here, we summarize the biophysics underlying the physiological expression of ITwindow, and describe how the ITwindow-mediated bistability in thalamic neurones is a key component in the generation of the slow (< 1 Hz) sleep rhythm (Hughes et al. 2002), one of the fundamental EEG activities in non-REM sleep dynamics (Steriade et al. 1993d). In a prospective outlook we will then consider how neuronal ITwindow may underlie other activities during the awake state. The distinct and important physiological roles that ITwindow plays in non-neuronal cells have been reviewed elsewhere (Lambert et al. 2001; Perez-Reyes, 2003).
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Biophysics of ITwindow
The window (or steady-state) component of an inactivating, voltage-dependent membrane current originates from the region of overlap (shaded in grey in Fig. 1Aa) between its steady-state activation and inactivation curves. In this voltage region, there is a fraction of channels which do not fully inactivate and therefore remain open. The estimated magnitude of the window current is strongly dependent on the steepness of these curves and their relative position with respect to the voltage axis (Fig. 1Aa). Since the activation and inactivation curves are obtained by fitting exponential functions to experimental measurements that in this voltage region are very small and highly dependent on the experimental conditions, great caution should be used in interpreting data on window currents. Furthermore, because these curves decay exponentially towards the voltage axis (i.e. they tend to zero at infinity) (Fig. 1Aa), all inactivating currents, including those with steady-state activation and inactivation curves that are far apart and shallow, possess a window current, even if extremely small. As has been the case for other inactivating currents, therefore, the issue is not whether neuronal ITwindow exists, but rather whether it has any physiological role, i.e. whether the small fraction of ‘non-inactivating’ neuronal T-type Ca2+ channels responsible for ITwindow makes any contribution to single neurone activities and neural network dynamics.
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Aa, steady-state activation and inactivation curves of IT from a TC neurone in vitro, showing in grey the region of overlap, i.e. the basis for ITwindow. b, plot of the absolute value of ITwindow (bell-shaped curve) and two Ileaks (blue and green lines). c, net current–voltage plot for the colour coded conditions depicted in b: bistability, i.e. two stable membrane potentials (filled and open circle), is present for the green but not for the blue line. d, plot of the small Ileak as in b and a small ITwindow (red curve) shows only one point of intersection. e, plot of the small Ileak and ITwindow as in d, but with two steady inward currents (continuous and dashed purple lines). f, net current–voltage plot for the colour coded conditions depicted in d and e: bistability is absent when IT is small (red line), but can be reintroduced by addition of a steady inward current that shifts the curve downwards (continuous purple line). A larger inward current further shifts the curve downwards with a loss of bistability and an instatement of a more depolarized membrane potential (open circle on dashed purple line). B, steady-state activation and inactivation curves for recombinant Cav3.1, Cav3.2 and Cav3.3 channels (a), and corresponding window currents (b). C, bistability is observed in TC neurones when Ih is blocked with ZD 7288. The transition from one to the other resting potential is achived by intracellular injection of current pulses. Da, following the block of IT with Ni2+, bistability is reintroduced in this TC neurone by using an amount of computer-generated IT commensurate with the theoretical prediction (i.e. the unfilled and filled circles of the green line in the voltage-net current plot match the two experimentally measured resting membrane potentials). A decrease in artificial gT to 140 nS (bottom records) abolishes the bistability as the voltage–net current plot now has only one resting membrane potential (filled circle of red line), as shown in Ab and Ad. However, using the same gT, bistability is reintroduced by the addition of a steady direct current (continuous purple line), as shown in Ae and Af. B used from Perez-Reyes, (2003) with permission ( 2003, American Physiological Society).
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A small, but clearly discernable, ITwindow was evident in the first studies that investigated native neuronal T-type Ca2+ channels (Carbone & Lux, 1984; Nowycky et al. 1985; Fox et al. 1987). Since then, ITwindow has been observed in many neuronal types (including the thalamic neurones on which this review will focus) (Coulter et al. 1989; Crunelli et al. 1989; Hernandez-Cruz & Pape, 1989) (Fig. 1Aa), using different preparations and techniques in both young and adult animals of different species (Huguenard, 1996; Perez-Reyes, 2003). From these data, ITwindow may be estimated to be generated by 0.05–0.8% of the total number of T-type channels in different CNS neurones. Recent investigations on recombinant Cav3.1, Cav3.2 and Cav3.3 channels (derived from the respective 1G, 1H and 1I pore forming subunits) have confirmed the results on native channels (Fig. 1Ba), and highlighted a larger ITwindow for Cav3.3 channels than for the other two types (Klockner et al. 1999) (Fig. 1Bb). These data are particularly important for thalamic cells, since glutamatergic thalamocortical (TC) neurones mostly express Cav3.1 and a very small number of Cav3.2 channels, whereas the GABAergic neurones of the nucleus reticularis thalami (NRT) are mainly endowed with Cav3.3 and much smaller amounts of Cav3.1 and Cav3.2 channels (Talley et al. 1999; Perez-Reyes, 2003).
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Neuronal ITwindow and membrane potential bistability
The transient activation of neuronal T-type Ca2+ channels generates the characteristic LTCP and associated high frequency burst firing. In contrast, the non-inactivating fraction of T-type Ca2+ channels leads, in the generally small membrane potential region of their expression, to a ‘steady’ influx of Ca2+ into the neurone, and thus to a ‘non-inactivating’ inward current (ITwindow) and a resulting ‘tonic’ depolarization. To fully appreciate the physiological significance of ITwindow in neuronal activity, however, it is necessary to consider the interaction between this current and the leak K+ current (Ileak) in the absence of other membrane currents. In Fig. 1Ab, the absolute amplitude of ITwindow (bell-shaped curve) has been plotted against the membrane potential, while two Ileaks are represented by the blue and green lines. When the slope of Ileak (i.e. gleak) is relatively small (green line in Fig. 1Ab), Ileak crosses the bell-shaped ITwindow curve in three points, at which both currents have equal values. Since ITwindow is an inward and Ileak an outward current, these are three points of zero net current (Fig. 1Ac): the leftmost and rightmost points are stable equilibrium points (filled and open circles on green line in Fig. 1Ac, respectively) whilst the middle point is unstable (i.e. grey circle in Fig. 1Ac). Under this condition the system generated by ITwindow and Ileak is bistable and, in the absence of other currents in this voltage region, neurones show two stable resting membrane potentials: one depolarized state where ITwindow is ‘on’ (open circle on green line in Fig. 1Ac) and a hyperpolarized state where ITwindow is ‘off’ (filled circle on green line in Fig. 1Ac). In contrast, when gleak is relatively large (blue line in Fig. 1Ab) Ileak crosses the ITwindow curve only in one point, which represents the resting membrane potential (filled circle on blue line in Fig. 1Ac).
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Clearly, changes in Ileak are not the only modifications that can bring about or remove ITwindow-mediated bistability. As shown in Fig. 1Ad, bistability is lost when a small Ileak interacts with a small ITwindow, which may result either from a reduction in gT, rightward and leftward shifts in its steady-state activation and inactivation curve, respectively, or a decrease in their steepness. This would give rise to a single equilibrium point (filled circle on red line in Fig. 1Af). Also important, both from a biophysical and physiological perspective, are the cases where in the absence of any change in both ITwindow and Ileak, bistability can be instated or eliminated by addition of a tonic current (Fig. 1Ae). For example, in the non-bistable system of Fig. 1Ad, addition of a steady inward current (continuous purple line in Fig. 1Ae) would shift the entire net current–voltage curve downwards (continuous purple line in Fig. 1Af), thus reintroducing bistability. Addition of a larger steady inward current (dashed purple line in Fig. 1Ae) would then remove bistability, moving the curve even further downwards and thus allowing only one resting membrane potential to exist (open circle on dashed purple line in Fig. 1Af).
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Physiological expression of ITwindow
Experimental confirmation of the presence of a physiologically relevant ITwindow has come from work in rat and cat TC neurones (Williams et al. 1997; Hughes et al. 1999; Hughes et al. 2002), of different sensory and motor thalamic nuclei (Blethyn et al. 2002), and NRT neurones (Blethyn et al. 2003). In these neurones bistability is observed after appropriate block of Ih (the most prominent current present within the voltage region where ITwindow is expressed), and, as predicted, appropriate voltage steps are able to switch the membrane potential between the two stable states (Williams et al. 1997) (Fig. 1C). This bistability is unaffected by Ba2+ and blockers of high threshold Ca2+ currents, including Cd2+, but is abolished by relatively small concentrations of Ni2+ (see Fig. 2D). The preferential block by Ni2+, compared to the lack of effect by similar concentrations of Cd2+, indicates that bistability is dependent on IT.
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A, bistability in computer simulations using a TC neurone model containing only IT and Ileak (upper trace). Note the similarity of the waveform to the experimental records in Fig. 1C. Addition of Ih leads to a continuous oscillation of the membrane potential (middle trace), the period of which is drastically affected by the further addition of ICAN to the model (lower trace). B, similarities of the slow (< 1 Hz) sleep oscillation observed in vitro and in vivo (the latter recorded simultaneously with the slow (< 1 Hz) rhythm in the EEG. C, in every TC neurone in vitro, the non-selective mGluR agonist (+/–)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD) elicits the slow (< 1 Hz) sleep oscillation, which is unaffected by the selective mGluR5 antagonist 2-methyl-G-(phenylethynyl) pyridine (MPEP), but blocked by the selective mGluR1a antagonist LY367385. D, block of the slow (< 1 Hz) sleep oscillation by Ni2+ but not by Cd2+. Downward deflections in the lowermost record are the neurone response to hyperpolarizing current pulses. E, the slow (< 1Hz) sleep oscillation recorded in an NRT neurone in vitro. B from contreras & Steriade (1995) with permission ( 1995 by the Society for Neuroscience). C and D from Sherman et al. (2001) with permission ( 2002, Elsevier).
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Additional and conclusive evidence for the involvement of ITwindow in the membrane potential bistability of thalamic neurones is provided by appropriately manipulating IT (and thus ITwindow) using the dynamic clamp (Hughes et al. 1999, 2002), a technique that allows a computer-generated current to be either added to, or subtracted from a living neurone (Sharp et al. 1993). Thus, in an originally bistable TC neurone where IT (and thus bistability) had been pharmacologically eliminated by Ni2+, bistability can be reinstated by adding an amount of computer-generated IT commensurate with the apparent Ileak of that neurone, such that the net current–voltage plot for that neurone satisfies the theoretical prediction (green line in Fig. 1Da). Similar dynamic clamp experiments (Hughes et al. 1999) also demonstrate that TC neurones lose their bistable properties by changes in artificial IT that decrease the size of ITwindow, for instance by moving apart the steady-state activation and inactivation curves of the computer generated IT by as little as 5 mV, or by reducing gT (red line in Fig. 1Da, see also Fig. 1Ad and Af). In the latter case, bistability could then be re-introduced by an appropriate change in direct current (continuous purple line in Fig. 1Ab), as explained in the previous section (see Fig. 1Ae and Af).
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ITwindow-mediated bistability is the cellular mechanism of the slow sleep ( 1 Hz) oscillation
As shown by computer simulations, addition of the hyperpolarization-activated current (Ih) drastically transforms the ITwindow–Ileak bistable system into a continuous oscillation of the membrane potential (Fig. 2A), by introducing a voltage-dependent, non-inactivating inward current. The period, and other properties of this oscillation, are also critically controlled by the presence of a Ca2+-dependent, non-selective cation current (ICAN) (Hughes et al. 2002) (Fig. 2A).
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This ITwindow-mediated, membrane potential oscillation is indeed the activity that is observed in TC and NRT neurones when Ih is not blocked (Fig. 2B). Extensive in vitro and in vivo studies (Hughes et al. 2002, 2004) have now shown it to represent the slow (< 1 Hz) sleep oscillation, i.e. the intracellularly recorded thalamic counterpart of the slow (< 1 Hz) sleep rhythm recorded in the EEG (Steriade et al. 1993a; Contreras & Steriade, 1995) (Fig. 2B). Both in animals (Steriade et al. 1993b) and in humans (Achermann & Borbely, 1997), this rhythm is one of the fundamental components of sleep dynamics during non-REM sleep, and a single slow (< 1 Hz) sleep oscillation cycle within the thalamocortical loop is now believed to underlie the expression of a K-complex in the EEG (Amzica & Steriade, 1997).
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The bistability, and the slow (< 1 Hz) sleep oscillation, however, can be seen in vitro only in a very small proportion (15%) of TC neurones under control conditions (Williams et al. 1997), but in 56% of TC neurones following electrical stimulation of the cortical afferents present in the slice (Hughes et al. 2002). Similarly, none of the TC neurones in vivo expresses the slow (< 1 Hz) oscillation following removal of the cortex (a condition similar to the in vitro situation), but the majority shows it when the cortex is left intact (Timofeev & Steriade, 1996). Together these in vitro and in vivo results show that the corticofugal afferents to TC neurones strongly contribute to setting the ITwindow–Ileak system to become bistable, either by changing Ileak or ITwindow, or adding/removing a tonic input (as shown schematically in Fig. 1Ab, d and e, respectively). In TC neurones that are non-oscillating in control conditions in vitro, the simple addition of direct current does not bring about the slow (< 1 Hz) sleep oscillation, and an increase in gT or a modification of its voltage region of expression (by manipulating the relative position of the steady-state activation and inactivation curves of computer-generated IT) does not satisfactorily reproduce all the properties of the slow (< 1 Hz) oscillation (Hughes et al. 1999). On the other hand, dynamic clamp experiments that decrease Ileak show an oscillation with identical characteristics to the one observed in vivo (Hughes et al. 1999). Indeed, it is the synaptic activation of metabotropic glutamate receptors (mGluR1a) that instates the decrease in Ileak necessary for establishing the ITwindow–Ileak bistable system, as also demonstrated in vivo and in vitro using selective mGluR agonists and antagonists (Hughes et al. 2002, 2004) (Fig. 2C).
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Figure 3 summarizes the cellular mechanism of the slow (< 1 Hz) sleep oscillation in TC neurones, where (i) ITwindow plays the major role by setting the level of the up (ITwindow ‘on’) and down (ITwindow ‘off’) states of the oscillation, (ii) Ih is responsible for repolarizing the neurone from the down state and thus critically determines the duration of the down state, and (iii) ICAN tightly controls the duration of the up state and is thus responsible for stabilizing the voltage region of existence of the slow oscillation (see Fig. 8 in Hughes et al. 2002). A very similar mechanism underlies the slow (< 1 Hz) sleep oscillation in NRT neurones (Fig. 2E), with ITwindow setting the basic levels for its up and down states (Blethyn et al. 2003).
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ITwindow-mediated bistability as a potential cellular mechanism of the high frequency bursts in the awake state
In the awake state, TC neurones are considerably more depolarized than during sleep, a situation similar to that depicted by the dashed purple line in Fig. 1Af where only one membrane potential exists (open circle) and bistability is not present. Computer simulations and in vitro experiments, however, have shown that even when the membrane potential of TC neurones is > –60 mV, a small EPSP (or IPSP) can temporarily bring the membrane potential into the voltage region where the ITwindow-mediated bistable mechanism could become transiently operational. This results in a stereotypical response consisting of a hyperpolarization (i.e. switching off of ITwindow) that is always terminated by an LTCP and associated high frequency burst firing (Fig. 4A and B), thus amplifying the output of TC neurones to small-amplitude, isolated, subthreshold synaptic potentials (Williams et al. 1997).
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A, computer simulations showing how at –60 mV two small EPSPs can evoke the stereotypical ITwindow-mediated response, consisting of a large hyperpolarization followed by an LTCP and high frequency firing. B, the same sequence of events as in A can be recorded in vitro in TC neurones. C, extracellular activity from a TC neurone of an awake behaving monkey showing high frequency bursts with putative characteristics of an LTCP-mediated event. C from Sherman (2001) with permission ( 2001, Elsevier).
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High frequency bursts have been shown to occur sporadically in some TC neurones of awake rats (Fanselow et al. 2001), guinea pigs (Massaux & Edeline, 2003), rabbits (Swadlow & Gusev, 2001), cats (Guido & Weyand, 1995) and monkeys (Ramcharan et al. 2000) (Fig. 4C), and often as part of the initial, though delayed, response to a sensory stimulus (Sherman, 2001). Although these bursts have been suggested to arise from the activation of T-type Ca2+ channels, no mechanism has been put forward to explain how this can occur from the relatively depolarized membrane potential that TC neurones occupy in the awake state. The ITwindow-mediated amplification described above might be one such explanation. In this scenario, the delay and the strength of the LTCP-mediated action potential burst would not be strictly set, but could be finely tuned by (i) the neurone's Ileak, which takes into account the overall background synaptic activity (Destexhe et al. 2001), (ii) the strength of Ih, which is known to be modulated by many thalamic transmitters (McCormick, 1992), and (iii) the number of T-type Ca2+ channels available for activation, which paradoxically is larger following a relatively prolonged period of depolarization (Leresche et al. 2004).
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Perspective outlook
The presence of Cav3.1, Cav3.2 and Cav3.3 channels in neurones of almost any brain region (Perez-Reyes, 2003) would support the notion that similar ITwindow-mediated activities as those described above for thalamic neurones may occur in various neuronal types throughout the brain. In particular, the ITwindow-mediated bistability might be the fundamental mechanism underlying the slow (< 1 Hz) sleep oscillation in neocortical cells (Steriade et al. 1993c), upon which synaptic influences would undoubtedly exert their modulation (Sanchez-Vives & McCormick, 2000).
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Although we have concentrated here on the electrical behaviours that occur as a result of the ITwindow-mediated bistability, one should not discard the potential presence of other physiologically relevant effects of ITwindow that are specifically linked to Ca2+ influx, for example the modulation of biochemical pathways and gene expression. With the known role of intracellular Ca2+ in short- and long-term neuronal plasticity, these actions could be of particular significance for thalamic and cortical neurones in view of recent data on the effect of the deep stages of non-REM sleep on memory (Huber et al. 2004).
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The discovery of a physiological role for ITwindow in thalamic neurones, and its likely involvement in the activities of many other neuronal types, clearly raise the question of potential alterations of this component of IT in neurological and psychiatric disorders. These could either be primary changes in IT that might contribute to pathophysiological conditions (Tsakiridou et al. 1995) or alterations in IT that are secondary to other abnormalities, such as extracellular pH changes (Shah et al. 2001), genetic mutations of other Ca2+ channels (Zhang et al. 2002), or continuous paroxysmal firing (Su et al. 2002).
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Footnotes
In memory of Eberhard H. Buhl. This report was presented at The Journal of Physiology Symposium in honour of the late Eberhard H. Buhl on Structure/Function Correlates in Neurons and Networks, Leeds, UK, 10 September 2004. It was commissioned by the Editorial Board and reflects the views of the authors.
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Zhang Y, Mori M, Burgess DL & Noebels JL (2002). Mutations in high-voltage-activated calcium channel genes stimulate low-voltage-activated currents in mouse thalamic relay neurons. J Neurosci 22, 6362–6371., http://www.100md.com(Vincenzo Crunelli, Tibor )