Voltage-gated calcium channels are important for thalamocortical (TC) oscillations related to spike-wave discharges (SWDs) during absence seizures. The role of Ca_V2.3 R-type channels expressed in the thalamic intralaminar complex in SWDs, however, is not well studied. We investigated pharmacologically induced SWDs from the central medial thalamus (CMT) and somatosensory cortex in a Ca_V2.3 knockout (KO) mouse model using local field potential (LFP), and electroencephalographic (EEG) recordings. The duration of cumulative SWDs was significantly decreased in Ca_V2.3 KO mice compared with wild-type (WT) mice. A characteristic increase in the delta and theta waves was observed in both the CMT and somatosensory cortex during SWDs with delta (1–4 Hz) band TC synchronization increasing only in WT animals. Specifically, in the KO mice, LFPs recorded from the CMT showed no significant changes in the delta band and a significant decrease in the theta (4–8 Hz) band, and cortical EEG recordings showed a significant increase in the delta band, but no changes in the theta band. The baseline TC phase synchronization in the delta band was also more pronounced in the Ca_V2.3 KO mice than in WT mice. These findings suggest that R-type calcium channels in the CMT play a crucial role in sustaining and promoting the oscillatory activity of the TC network during absence seizures.

The potential contribution of the ion channels that control the excitability of the midline and intralaminar nuclei of the thalamus to the modulation of behaviors has not been well studied. In this study, we used both global genetic deletion (knock-out, KO) and thalamus-specific molecular knock-down (KD) approaches to investigate the role of thalamic Ca_V3.1 T-type calcium channels (T-channels) in fear learning and fear responses. Previously, we have shown that the dominant subtype of T-channels in the central medial nucleus of the thalamus (CMT) is the Ca_V3.1 isoform and that CMT neurons from Ca_V3.1 KO animals have decreased burst firing. By specifically knocking down Ca_V3.1 T-channels in the CMT using the shRNA approach, we also reduced burst firing without affecting the tonic firing mode of the transfected neurons. We report that global Ca_V3.1 KO animals showed stronger freezing behaviors during both the conditioning and testing phases of contextual fear conditioning, while CMT-specific Ca_V3.1 KD mice only had stronger fear responses during testing. In contrast, the cue-mediated fear responses were similar between Ca_V3.1 KO and Ca_V3.1 KD mice and the controls. Our findings validate thalamic Ca_V3.1 T-channels as a potential new target for the development or treatment of different psychiatric diseases, such as post-traumatic stress disorder, schizophrenia, anxiety, and substance abuse disorders.

Although substantial progress has been made in the last three decades towards our understanding of how general anesthetics (GAs) act at the molecular level, much less is known about how GAs cause loss of consciousness at the level of neuronal networks. The role of thalamus as an important brain region in anesthetic-induced hypnosis is relatively well established, but the specific roles of voltage-gated ion channels in different functional regions of the thalamus in anesthetic mechanisms are not well studied. To address this gap in knowledge, we selectively silenced the Cacna1g gene that encodes the low-threshold-activated Ca_V3.1 T-type voltage-gated calcium channel subunit by injecting short-hairpin RNA (shRNA) into midline and intralaminar - nonspecific thalamus (MIT) and sensory - specific ventrobasal (VB) thalamic nuclei in wild-type (WT) mice. Control animals were injected with scrambled shRNA. To validate our silencing approach, we performed patch-clamp experiments in acute thalamic slices ex vivo. In injected animals we determined anesthetic endpoints such as hypnosis measured with loss of righting reflex (LORR) and immobilization measured with loss of withdrawal reflex (LOWR) in vivo after administration of a traditional volatile GA isoflurane. Effective Ca_V3.1 channel knock-down was documented by greatly diminished amplitudes of T-currents and absence of rebound burst firing in our patch-clamp recordings from thalamic slices. We found that knocking down Ca_V3.1 channels in MIT significantly decreased inhaled isoflurane concentration that is required to induce LORR, but it did not affect speed of anesthetic induction and the immobilizing effect of isoflurane. In contrast, knocking down the Ca_V3.1 channel in the VB thalamus did not affect any of the measured anesthetic endpoints. Hence, we concluded that Ca_V3.1 channels in nonspecific MIT thalamus have a preferential role in anesthetic hypnosis when compared to the sensory VB thalamus.