The CaV 2.3 r-type voltage-gated Ca2+ Channel n mouse sleep architecture

Abstract

Study Objectives: Voltage-gated Ca2+ channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca2+ channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. Highvoltage activated (HVA) CaV 1 L-type Ca2+ channels, on the opposite, favor the tonic mode of action associated with higher levels of vigilance. However, the role of the HVA Non-L-type CaV 2.3 Ca 2+ channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV 2.3/ mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV 2.3 mediated Ca2+ influx into RTN neurons can trigger small-conductance Ca 2+-Activated K+-channel type 2 (SK2) currents capable of maintaining thalamic burst activity. Based on these studies we investigated the role of CaV 2.3 R-type Ca2+ channels in rodent sleep. Methods: The role of CaV 2.3 Ca2+ channels was analyzed in Ca V 2.3/ mice and controls in both spontaneous and artificial urethane-induced sleep, using implantable video-EEG radiotelemetry. Data were analyzed for alterations in sleep architecture using sleep staging software and timefrequency analysis. Results: CaV 2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS). Whereas mean sleep stage durations remained unchanged, the total number of SWS epochs was increased in CaV 2.3/ mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV 2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV 3 T-type Ca2+ channel expression. The detailed mechanisms of SWS increase in CaV 2.3/ mice remain to be determined. Conclusions: Low-voltage activated CaV 2.3 R-type Ca2+ channels in the thalamocortical loop and extra-thalamocortical circuitries substantially regulate rodent sleep architecture thus representing a novel potential target for pharmacological treatment of sleep disorders in the future.