Intrathalamic rhythmicity studied in vitro: nominal T-current modulation causes robust antioscillatory effects

Abstract

Thalamocortical oscillations mediate both physiological and pathophysiological behaviors including sleep and generalized absence epilepsy (GA). Reciprocal intrathalamic circuitry and robust burst firing, dependent on underlying transient Ca current (IT) in thalamic neurons, support generation of such rhythms. In order to study the regulation of intrathalamic rhythm generation and the effects of GA anticonvulsants previously shown to reduce IT in acutely isolated thalamic neurons, we developed an in vitro rat thalamic slice preparation that retains sufficient intrathalamic circuitry to support evoked oscillations (range = 2.0-4.6 Hz, average = 2.7, n = 38), associated with burst firing in the thalamic reticular nucleus (nRt) and thalamic relay neurons. Extracellular stimulation of nRt evoked in relay neurons a biphasic inhibitory response with prominent GABAA and GABAB receptor-mediated components. The GABAA component was picrotoxin sensitive, outwardly rectifying and Cl- dependent, with a very negative reversal potential (-94 mV), indicating that an active extrusion mechanism exists in these cells to keep [Cl-]i < 5 mM. The GABAB component had a linear conductance, a reversal potential of -103 mV, and was quite long lasting (about 300 msec) so that rebound bursts often were generated on its decay phase, presumably leading to reexcitation of nRt through known excitatory connections. GABAB-mediated responses thus provide a timing mechanism for promoting slow intrathalamic oscillations. Reduction of IT (30-40%) by succinimides slightly increased the threshold for burst generation in relay and nRt cells, but there was little effect on either number of spikes/burst or intraburst frequency, and there were no other direct effects on other measures of cellular excitability. Intrathalamic oscillations were significantly reduced by these agents through a slight decrease in burst probability of thalamic neurons. We conclude that interactions between the intrinsic properties of thalamic neurons and intrathalamic circuitry lead to generation of slow oscillations. A similar mechanism may underlie the pathophysiological 3 Hz spike and wave EEG activity that characterizes GA. Furthermore, anti-GA drugs such as ethosuximide probably exert their action by reducing the burst-firing probability of neurons within populations of reciprocally interconnected relay and nRt neurons, thus producing a desynchronization of the thalamic circuit that prevents spike/wave generation.

Interaction between neocortical and hippocampal networks via slow oscillations

“…If the reticular thalamic nucleus is either damaged or disconnected from the neocortex, sleep spindles are no longer observed either in the thalamus or in the neocortex Steriade et al, 1987;Buzsáki et al, 1988). Rhythmic bursts produced by RE neurons result in large IPSPs in thalamo-cortical cells, sufficient to generate rebound low-threshold Ca 2+ bursts, which, in turn, produce long-lasting EPSPs in thalamic reticular cells and trigger the next oscillatory cycle (Deschenes et al, 1984;Buzsáki, 1991;Bal and McCormick, 1993;Huguenard and Prince, 1994;von Krosigk et al, 1993).…”

NPY signaling through Y1 receptors modulates thalamic oscillations

“…Extracellular recordings were performed as described previously [14,25]. Briefly, thalamic slices were transferred to an interface recording chamber and superfused with modified ACSF containing 1 mM MgCl 2 , 0.02 mM bicuculline methiodide and 0.5 mM L-glutamine (both Sigma).…”

“…Blockade of GABA A receptors transforms sleep spindle like oscillations into slower, spike-wave like activity. Experimentally, ~3 Hz, spike-wave like oscillations can readily be evoked in thalamic slices from young rats (P13-P15) by delivering single extracellular stimuli to the internal capsule, the main corticothalamic and thalamocortical fiber tract [14]. 3 Hz thalamic oscillations are an in vitro model of absence (spike-wave) seizures in rats as well as in primates [28,29].…”

Anatomical and physiological considerations in thalamic rhythm generation

“…Thalamic slices were prepared as described (Huguenard and Prince 1994b;Ulrich and Huguenard 1996a). Briefly, 9±15-day-old rat pups (Sprague±Dawley) of either sex were anesthetized (50 mg/kg pentobarbital, i.p.)…”

“…A number of pre and post-synaptic factors combine to produce powerful postsynaptic inhibition. The first factor, as mentioned above, is the burst firing ability of nRt neurons, which leads to a rapid succession of individual IPSPs (Huguenard and Prince 1994b;Sanchez-Vives et al 1997a), each corresponding to individual action potentials in nRt cells. Under these conditions, individual IPSPs summate to produce large compound responses mediated by two types of GABA receptors.…”