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VOLUME 36, ISSUE 01

SLEEP AND ADENOSINERGIC SENSITIVITY IN CACNA1A R192Q MUTANT MICE
Reduced Sleep and Low Adenosinergic Sensitivity in Cacna1a R192Q Mutant Mice

http://dx.doi.org/10.5665/sleep.2316

Tom Deboer, PhD1; Hester C. van Diepen, MSc1; Michel D. Ferrari, MD, PhD2; Arn M. J. M. Van den Maagdenberg, PhD2,3; Johanna H. Meijer, PhD1

1Laboratory for Neurophysiology, Department of Molecular Cell Biology; 2Department of Neurology, and; 3Department of Human Genetics; Leiden University Medical Center, Leiden, The Netherlands.



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Study Objectives:

Adenosine modulates sleep via A1 and A2A receptors. As the A1 receptor influences CaV2.1 channel functioning via G-protein inhibition, there is a possible role of the CaV2.1 channel in sleep regulation. To this end we investigated transgenic Cacna1a R192Q mutant mice that express mutant CaV2.1 channels that are less susceptible to inhibition by G-proteins. We hypothesized that Cacna1a R192Q mice could show reduced susceptibility to adenosine, which may result in a sleep phenotype characterized by decreased sleep.

Design:

R192Q mutant and littermate wild-type mice were subjected to a 6-h sleep deprivation, treatment with caffeine (a non-specific adenosine receptor antagonist which induces waking), or cyclopentyladenosine (CPA, an A1 receptor specific agonist which induces sleep).

Measurements and Results:

Under baseline conditions, Cacna1a R192Q mice showed more waking with longer waking episodes in the dark period and less non-rapid eye movement (NREM) sleep, but equal amounts of REM sleep compared to wild-type. After treatment with caffeine R192Q mice initiated sleep 30 min earlier than wild-type, whereas after CPA treatment, R192Q mice woke up 260 min earlier than wild-type. Both results indicate that Cacna1a R192Q mice are less susceptible to adenosinergic input, which may explain the larger amount of waking under undisturbed baseline conditions.

Conclusion:

We here show that adenosinergic sleep induction, and responses to caffeine and CPA, are modified in the R192Q mutant in a manner consistent with decreased susceptibility to inhibition by adenosine. The data suggest that the A1 receptor modulates sleep via the CaV2.1 channel.

Citation:

Deboer T; van Diepen HC; Ferrari MD; Van den Maagdenberg AMJM; Meijer JH. Reduced sleep and low adenosinergic sensitivity in Cacna1a R192Q mutant mice. SLEEP 2013;36(1):127-136.

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