Neurons of the reticular thalamus (RT) display oscillatory burst discharges that are believed to be critical for thalamocortical network oscillations related to absence epilepsy. Ca²+-dependent mechanisms underlie such oscillatory discharges. However, involvement of high-voltage activated (HVA) Ca²+ channels in this process has been discounted. We examined this issue closely using mice deficient for the HVA Ca(v)2.3 channels. In brain slices of Ca(v)2.3⁻/⁻, a hyperpolarizing current injection initiated a low-threshold burst of spikes in RT neurons; however, subsequent oscillatory burst discharges were severely suppressed, with a significantly reduced slow afterhyperpolarization (AHP). Consequently, the lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to γ-butyrolactone-induced absence epilepsy. Local blockade of Ca(v)2.3 channels in the RT mimicked the results of Ca(v)2.3⁻/⁻ mice. These results provide strong evidence that Ca(v)2.3 channels are critical for oscillatory burst discharges in RT neurons and for the expression of absence epilepsy.

Endogenous opioids generate analgesic signals in the periaqueductal gray (PAG). However, because cell types in the PAG are difficult to identify, its neuronal mechanism has remained poorly understood. To address this issue, we characterized PAG neurons by their electrical properties using differentially labeled GABAergic and output neurons in the PAG. We found that GABAergic neurons were mostly fast-spiking cells and could be further divided into two distinct classes: with or without low-threshold spikes (LTS) driven by T-type channels. In contrast, the PAG output neurons lacked LTS and showed heterogeneous firing patterns. To reveal the function of the LTS, we examined the mutant mice lacking the α1G T-type channels (α1G). The mutant mice lacked LTS in the fast-spiking GABAergic neurons of the PAG and unexpectedly showed impaired opioid-dependent analgesia; a similar phenotype was reproduced in PAG-specific α1G-knockdown mice. Electrophysiological analyses revealed functional expression of μ-opioid receptors in the low threshold-spiking GABAergic neurons. These neurons in the mutant lacking LTS showed markedly enhanced discharge activities, which led to an augmented inhibition of output neurons. Furthermore, the impaired analgesia observed in α1G −/− mice was reversed by blocking local GABA A receptors. These results indicate that α1G T-type channels are critical for the opioidergic descending analgesia system in the PAG.opioid-descending analgesia | α1G | morphine | stress | calcium-activated potassium channel | afterhyperpolarization

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...