Rebound burst firing in the reticular thalamus is not essential for pharmacological absence seizures in mice

Abstract

Intrinsic burst and rhythmic burst discharges (RBDs) are elicited by activation of T-type Ca 2+ channels in the thalamic reticular nucleus (TRN). TRN bursts are believed to be critical for generation and maintenance of thalamocortical oscillations, leading to the spikeand-wave discharges (SWDs), which are the hallmarks of absence seizures. We observed that the RBDs were completely abolished, whereas tonic firing was significantly increased, in TRN neurons from mice in which the gene for the T-type Ca 2+ channel, Ca V 3.3, was deleted (Ca V 3.3 −/− ). Contrary to expectations, there was an increased susceptibility to drug-induced SWDs both in Ca V 3.3 −/− mice and in mice in which the Ca V 3.3 gene was silenced predominantly in the TRN. Ca V 3.3 −/− mice also showed enhanced inhibitory synaptic drive onto TC neurons. Finally, a double knockout of both Ca V 3.3 and Ca V 3.2, which showed complete elimination of burst firing and RBDs in TRN neurons, also displayed enhanced drug-induced SWDs and absence seizures. On the other hand, tonic firing in the TRN was increased in these mice, suggesting that increased tonic firing in the TRN may be sufficient for druginduced SWD generation in the absence of burst firing. These results call into question the role of burst firing in TRN neurons in the genesis of SWDs, calling for a rethinking of the mechanism for absence seizure induction.A bsence seizures are generalized, nonconvulsive seizures characterized by the appearance of bilaterally synchronous spike-and-wave discharges (SWDs) on the electroencephalogram (EEG). The frequency of the SWDs is variable among different models and is usually higher (4-12 Hz) in rodents than in humans (3 Hz) (1). SWDs represent synchronized oscillations of the thalamocortical network (2-4), a network that includes neurons of the cerebral cortex, thalamocortical nucleus (TC), and thalamic reticular nucleus (TRN) (5). This thalamocortical circuitry is a key CNS structure for gating the flow of sensory information from the periphery to the cortex (6, 7). Both thalamocortical and corticothalamic connections are mainly glutamatergic (8). The TRN is a shell-like structure that covers most of the rostral, lateral, and ventral parts of the thalamus (5) and is composed exclusively of GABAergic interneurons that provide massive inhibitory input to TC neurons (9). The most distinctive feature of thalamocortical circuitry is its intrinsic ability to generate oscillations via the reciprocal circuits between TC and TRN neurons (10-12).Both TC and TRN neurons are able to generate two distinctive patterns of action potential firing: tonic and burst (13,14). Burst firing is mediated by low-voltage-activated (LVA) T-type Ca 2+ channels (15). There are three subtypes of T-type Ca 2+ channels, called Ca V 3.1, Ca V 3.2, and Ca V 3.3, each with distinctive expression patterns and kinetic properties (16). Within the thalamocortical circuit, Ca V 3.1 channels are predominantly expressed in TC neurons, whereas Ca V 3.2 and Ca V 3.3 channels are expressed only in TR...

CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy

“…In this study, we examined the regulation and function of Ca V 3.2 channels in multiple distinct types of central neurons in intact circuits and intact brains. We discovered that, in contrast to Ca V 3.1 and Ca V 3.3 channels, which are essential for generating low-threshold calcium spikes (Kim et al 2001;Astori et al 2011;Lee et al 2014a), Ca V 3.2 channels did not modulate membrane properties or contribute to low-threshold calcium spikes, presumably due to the relatively restricted expression of only a small number of functional Ca V 3.2 channels at the synapses in central neurons (Fig. 5).…”

“…Both the Ca V 3.1 and Ca V 3.3 channels contribute to the lowthreshold calcium currents in central neurons (Kim et al 2001;Astori et al 2011;Lee et al 2014a). These low-threshold calcium currents can promote burst synchronization with low-threshold calcium spikes and calcium-dependent potassium conductance and potentiate synaptic AMPA-R-mediated transmission with depolarization (Catterall 2011;Cheong and Shin 2013;Simms and Zamponi 2014).…”

Heantos-4, a natural plant extract used in the treatment of drug addiction, modulates T-type calcium channels and thalamocortical burst-firing

“…Further, in mice following genetic ablation of the Cacna1i gene, encoding Ca V 3.3 the T-type current is approximately 40% of the total T-type current in TRN neurons of wild-type mice [38]. In a separate study investigating a strain of mice lacking the Ca V 3.3 channel, T-type calcium currents were attenuated by approximately 80% in comparison to wild-type mice, although low threshold bursts could still be elicited in 75% of animals [39]. Of note, the remaining T-type calcium current is absent and burst-firing abolished in double Ca V 3.2/Ca V 3.3 knockout mice [39].…”

“…In a separate study investigating a strain of mice lacking the Ca V 3.3 channel, T-type calcium currents were attenuated by approximately 80% in comparison to wild-type mice, although low threshold bursts could still be elicited in 75% of animals [39]. Of note, the remaining T-type calcium current is absent and burst-firing abolished in double Ca V 3.2/Ca V 3.3 knockout mice [39]. Taken together Ca V 3.2 currents are predicted to contribute 20-40% of the total T-type calcium channel current in TRN neurons, with the remaining current contributed by the Ca V 3.3 isoform.…”

Progress in the molecular mechanisms of genetic epilepsies using patient‐induced pluripotent stem cells

“…Classic GE syndromes include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic seizures alone (GTCS). A recent study using human genetic screening and animal experiments confirmed that CAE and JAE are associated with multiple combined mutations in T‐type calcium channels and γ‐aminobutyric acid (GABA) A receptors rather than single‐gene mutations . In addition, gene mutations in several proteins other than ion channels can also cause seizures through spikes in discharges that create abnormal neural circuits in the cortex and thalamus .…”