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VOLUME 39, ISSUE 12

BASIC SCIENCE
Sleep Homeostatic and Waking Behavioral Phenotypes in Egr3-Deficient Mice Associated with Serotonin Receptor 5-HT2 Deficits

http://dx.doi.org/10.5665/sleep.6324

Janne Grønli, PhD1,2,3; William C. Clegern, BS1; Michelle A. Schmidt, MS1; Rahmi S. Nemri, BS1; Michael J. Rempe, PhD2,4; Amelia L. Gallitano, MD, PhD5; Jonathan P. Wisor, PhD1,2

1Elson S. Floyd College of Medicine, Department of Biomedical Sciences, Washington State University, Spokane, WA; 2Sleep and Performance Research Center, Washington State University; 3Department of Biological and Medical Psychology, University of Bergen, Norway; 4Mathematics and Computer Science, Whitworth University, Spokane, WA; 5Department of Basic Medical Sciences and Psychiatry, University of Arizona College of Medicine-Phoenix, Phoenix, AZ



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Study Objective:

The expression of the immediate early gene early growth response 3 (Egr3) is a functional marker of brain activity including responses to novelty, sustained wakefulness, and sleep. We examined the role of this gene in regulating wakefulness and sleep.

Methods:

Electroencephalogram/electromyogram (EEG/EMG) were recorded in Egr3-/- and wild-type (WT) mice during 24 h baseline, 6 h sleep disruption and 6 h recovery. Serotonergic signaling was assessed with 6 h EEG/EMG recordings after injections of nonselective 5-HT2 antagonist (clozapine), selective 5-HT2 antagonists (5-HT2A; MDL100907 and 5-HT2BC; SB206553) and a cocktail of both selective antagonists, administered in a randomized order to each animal.

Results:

Egr3-/- mice did not exhibit abnormalities in the timing of wakefulness and slow wave sleep (SWS); however, EEG dynamics in SWS (suppressed 1–3 Hz power) and in quiet wakefulness (elevated 3–8 Hz and 15–35 Hz power) differed in comparison to WT-mice. Egr3-/- mice showed an exaggerated response to sleep disruption as measured by active wakefulness, but with a blunted increase in homeostatic sleep drive (elevated 1–4 Hz power) relative to WT-mice. Egr3-/-mice exhibit greatly reduced sedative effects of clozapine at the electroencephalographic level. In addition, clozapine induced a previously undescribed dissociated state (low amplitude, low frequency EEG and a stable, low muscle tone) lasting up to 2 h in WT-mice. Egr3-/- mice did not exhibit this phenomenon. Selective 5-HT2A antagonist, alone or in combination with selective 5-HT2BC antagonist, caused EEG slowing coincident with behavioral quiescence in WT-mice but not in Egr3-/- mice.

Conclusion:

Egr3 has an essential role in regulating cortical arousal, wakefulness, and sleep, presumably by its regulation of 5-HT2 receptors.

Citation:

Grønli J, Clegern WC, Schmidt MA, Nemri RS, Rempe MJ, Gallitano AL, Wisor JP. Sleep homeostatic and waking behavioral phenotypes in Egr3-deficient mice associated with serotonin receptor 5-HT2 deficits. SLEEP 2016;39(12):2189–2199.

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