Deletion of the Wolfram syndrome-related gene Wfs1 results in increased sensitivity to ethanol in female mice.
Wolfram syndrome, induced by mutation in WFS1 gene, increases risk of developing mood disorders in humans. In mice, Wfs1 deficiency cause higher anxiety-like behaviour and increased response to anxiolytic-like effect of diazepam, a GABAA receptor agonist. As GABAergic system is also target for ethanol, we analysed its anxiolytic-like and sedative properties in Wfs1-deficient mice using elevated plus-maze test and tests measuring locomotor activity and coordination, respectively. Additionally loss of righting reflex test was conducted to study sedative/hypnotic properties of ethanol, ketamine and pentobarbital. To evaluate pharmacokinetics of ethanol in mice enzymatic colour test was used. Finally, gene expression of alpha subunits of GABAA receptors following ethanol treatment was studied by real-time-PCR. Compared to wild-types, Wfs1-deficient mice were more sensitive to ethanol-induced anxiolytic-like effect, but less responsive to impairment of motor coordination. Ethanol and pentobarbital, but not ketamine, caused longer duration of hypnosis in Wfs1-deficient mice. The expression of Gabra2 subunit at 30 minutes after ethanol injection was significantly increased in the frontal cortex of Wfs1-deficient mice as compared to respective vehicle-treated mice. For the temporal lobe, similar change in Gabra2 mRNA occurred at 60 minutes after ethanol treatment in Wfs1-deficient mice. No changes were detected in Gabra1 and Gabra3 mRNA following ethanol treatment. Taken together, increased anxiolytic-like effect of ethanol in Wfs1-deficient mice is probably related to altered Gabra2 gene expression. Increased anti-anxiety effect of GABAA receptor agonists in the present work and earlier studies (Luuk et al., 2009) further suggests importance of Wfs1 gene in the regulation of emotional behaviour.
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia. Electronic address: sirli.raud@ut.ee.
Sirli
S
Raud
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Riin
R
Reimets
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Maarja
M
Loomets
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Silva
S
Sütt
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Alina
A
Altpere
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Tanel
T
Visnapuu
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Jürgen
J
Innos
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Hendrik
H
Luuk
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Mario
M
Plaas
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Vallo
V
Volke
Department of Physiology, Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia; Centre for Excellence in Translational Medicine, University of Tartu, Estonia.
Eero
E
Vasar
D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics / Q000494:pharmacology*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D013702:Temporal Lobe / Q000187:drug effects / Q000378:metabolism; D014929:Wolfram Syndrome / Q000235:genetics
D002492:Central Nervous System Depressants; D058785:GABA-A Receptor Agonists; C546241:Gabra1 protein, mouse; C493920:Gabra2 protein, mouse; C546258:Gabra3 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C114987:wolframin protein; D000431:Ethanol; D007649:Ketamine; D010424:Pentobarbital
Elevated plus-maze; Ethanol; GABA(A) receptor; Gene expression; Loss of righting reflex; Wfs1-deficient mice