The CaV2.3 R-type voltage-gated Ca2+ channel in mouse sleep architecture.
OBJECTIVE
Voltage-gated Ca(2+) channels (VGCCs) are key elements in mediating thalamocortical rhythmicity. Low-voltage activated (LVA) CaV 3 T-type Ca(2+) channels have been related to thalamic rebound burst firing and to generation of non-rapid eye movement (NREM) sleep. High-voltage activated (HVA) CaV 1 L-type Ca(2+) 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 CaV2.3 Ca(2+) channels, which are predominantly expressed in the reticular thalamic nucleus (RTN), still remains unclear. Recently, CaV2.3(-/-) mice were reported to exhibit altered spike-wave discharge (SWD)/absence seizure susceptibility supported by the observation that CaV2.3 mediated Ca(2+) 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 CaV2.3 R-type Ca(2+) channels in rodent sleep.


METHODS
The role of CaV2.3 Ca(2+) channels was analyzed in CaV2.3(-/-) 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 time-frequency analysis.


RESULTS
CaV2.3 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 CaV2.3(-/-) mice. Additional changes were observed for sleep stage transitions and EEG amplitudes. Furthermore, urethane-induced SWS mimicked spontaneous sleep results obtained from CaV2.3 deficient mice. Quantitative Real-time PCR did not reveal changes in thalamic CaV3 T-type Ca(2+) channel expression. The detailed mechanisms of SWS increase in CaV2.3(-/-) mice remain to be determined.


CONCLUSIONS
Low-voltage activated CaV2.3 R-type Ca(2+) 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.
Federal Institute for Drugs and Medical Devices, Bonn, BfArM, Germany.
Magdalena Elisabeth
ME
Siwek
Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
Ralf
R
Müller
Federal Institute for Drugs and Medical Devices, Bonn, BfArM, Germany.
Christina
C
Henseler
Federal Institute for Drugs and Medical Devices, Bonn, BfArM, Germany.
Karl
K
Broich
Federal Institute for Drugs and Medical Devices, Bonn, BfArM, Germany.
Anna
A
Papazoglou
Federal Institute for Drugs and Medical Devices, Bonn, BfArM, Germany ; Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
Marco
M
Weiergräber
D000818:Animals; D020908:Calcium Channels, R-Type / Q000235:genetics / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D004569:Electroencephalography; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010507:Periodicity; D012890:Sleep / Q000502:physiology*; D012894:Sleep Stages / Q000502:physiology; D013788:Thalamus / Q000166:cytology / Q000502:physiology
C498916:Cacna1e protein, mouse; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins
rapid eye movement (REM); slow-wave sleep (SWS); thalamocortical circuitry; vigilance