T-type calcium channels mediate the transition between tonic and phasic firing in thalamic neurons.

Abstract

Thalamic neurons undergo a shift from tonic to phasic (burst) firing upon hyperpolarization. This state transition results from deinactivation of a regenerative depolarizing event referred to as the low-threshold spike. Isolated adult guinea pig thalamic (dorsal lateral geniculate) neurons exhibited low-threshold spikes that could be blocked by low concentrations of nickel but were unaffected by the dihydropyridine nimodipine. Whole-cell voltage-clamp recordings from these cells demonstrated a low-threshold, rapidly inactivating (T) Ca2+ current that manifested similar voltage dependency and time course as the low-threshold spike. Like lowthreshold spikes, the T-type Ca2' current was eliminated by nickel but was unaffected by nimodipine. In thalamic neurons, T-type Ca2+ channels underlie the low-threshold spike and, therefore, play a critical role in regulating the firing pattern of these cells.Thalamic neurons exhibit two distinct response modes to afferent excitation (1,2). At normal resting potentials these cells respond with a linear depolarization that faithfully follows the input signal and may result in the continuous discharge of Na+-dependent action potentials in a manner referred to as tonic firing. Upon hyperpolarization an abrupt transition to a nonlinear response state occurs in which firing is blocked for at least 50-100 msec between single or grouped spikes so that the cells fire in a phasic (burst) mode (3, 4). Tonic firing is the pattern most frequently recorded from thalamic neurons in awake animals, whereas phasic firing is typical of slow-wave sleep and may account for the accompanying spindling in the cortical electroencephalogram (5). The shift to phasic firing occurs as a result of deinactivation of a broad, low-amplitude regenerative response, referred to as the low-threshold spike (LTS). Recently, the stimulus for deinactivation of the LTS has been demonstrated to be a prolonged period of synaptically mediated inhibition (6, 7). The LTS is resistant to tetrodotoxin (TTX), a blocker of Na+-dependent action potentials, but is sensitive to inorganic Ca2+ channel antagonists and is, therefore, presumably dependent upon Ca2' entry (8). However, characterization of the Ca2+ channels underlying the LTS has been hampered by the lack of a preparation allowing voltage-clamp recording with adequate spatial voltage control. Recently, methods were developed for isolating intact neuron cell bodies from slices of the adult mammalian brain (9). On the basis of recordings from freshly isolated guinea pig thalamic neurons, we now present evidence that the LTS results from activation ofT-type voltage-gated Ca2+ channels with properties similar to those in other neuronal and nonneuronal cell types (10). METHODSThese experiments were done by using isolated neuron cell bodies obtained by enzymatic dissociation of guinea pig dorsal lateral geniculate nucleus (LGNd) slices (Fig. 1). Cells were prepared by a modification of the method of Kay and Wong (9) from slices (0.3-0.5 x 1 x 3 mm) of the LGNd of 25...

Role of L‐Type Calcium Channel Modulation in Nonconvulsive Epilepsy in Rats

“…The rhythmic bursting of thalamic neurons is specifically dependent on the T-type calcium channel, as demonstrated by many in vitro studies (Jahnsen and Llings, 1984;Steriade and Llinas, 1988;Coulter et al, 1990;Avanzini et al, 1992). Suzuki and Rogawski (1989) showed that these thalamic oscillations could be blocked by T-type calcium channel blockers. Coulter et al confirmed the involvement of T-type channels in oscillations and in absence epilepsy by showing that ESM, a drug that selectively protects against absence epilepsy, specifically inhibits T-type channels (Coulter et al, 1989a(Coulter et al, ,1989b); thus ample evidence shows that T-type calcium channel blockade inhibits thalamic oscillations.…”

“…Bay K 8644, a dihydropyridine derivative, increases the opening probability of a particular subclass of calcium channels, the L-type channel, thereby promoting voltage-dependent calcium influx (Bernath, 1992). On the other hand, nimodipine also belongs to the class of dihydropyridines, but this centrally active drug acts as a calcium antagonist by blocking the voltage-dependent L-type calcium channels (Meyer et al, 1987;Suzuki and Rogawski, 1989). Spedding and Paoletti (1992) suggest that BAY K 8644 and nimodipine are rather selective for the L-type calcium channels.…”

Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels

“…Considerable evidence suggests that spike-wave discharges are produced by synchronized oscillations of cortical, reticular thalamic, and corticothalamic neurons (92,136,378). Spike-wave discharges of corticothalamic neurons are in part mediated by T-type channels that produce LTS (93,277,377,387). Ethosuximide is a first-line drug in the treatment of absence epilepsy (193).…”

Generalized Epileptic Disorders: An Update

“…The rhythmic volleys traveling along the reticular cell axons induce GABA A -and GABA B -mediated hyperpolarizing inhibitory postsynaptic potentials (IPSPs) in relay neurons. As the membrane potential hyperpolarization of the relay neurons decays toward the resting level, a T-type Ca 2+ current is generated that triggers bursts of action potentials (76)(77)(78)(79)(80). In addition, a noninactivating Na + -current component may act synergistically with the T-type Ca 2+ current in the generation of bursting (81).…”