title: Sex-dependent adaptive changes in serotonin-1A autoreceptor function and anxiety in Deaf1-deficient mice.
abstract: The C (-1019) G rs6295 promoter polymorphism of the serotonin-1A (5-HT1A) receptor gene is associated with major depression in several but not all studies, suggesting that compensatory mechanisms mediate resilience. The rs6295 risk allele prevents binding of the repressor Deaf1 increasing 5-HT1A receptor gene transcription, and the Deaf1-/- mouse model shows an increase in 5-HT1A autoreceptor expression. In this study, Deaf1-/- mice bred on a mixed C57BL6-BALB/c background were compared to wild-type littermates for 5-HT1A autoreceptor function and behavior in males and females. Despite a sustained increase in 5-HT1A autoreceptor binding levels, the amplitude of the 5-HT1A autoreceptor-mediated current in 5-HT neurons was unaltered in Deaf1-/- mice, suggesting compensatory changes in receptor function. Consistent with increased 5-HT1A autoreceptor function in vivo, hypothermia induced by the 5-HT1A agonist DPAT was augmented in early generation male but not female Deaf1-/- mice, but was reduced with succeeding generations. Loss of Deaf1 resulted in a mild anxiety phenotype that was sex-and test-dependent, with no change in depression-like behavior. Male Deaf1 knockout mice displayed anxiety-like behavior in the open field and light-dark tests, while female Deaf1-/- mice showed increased anxiety only in the elevated plus maze. These data show that altered 5-HT1A autoreceptor regulation in male Deaf1-/- mice can be compensated for by generational adaptation of receptor response that may help to normalize behavior. The sex dependence of Deaf1 function in mice is consistent with a greater role for 5-HT1A autoreceptors in sensitivity to depression in men.
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), Ottawa, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Luckhart
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), Ottawa, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Philippe
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), Ottawa, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Brice
authors.initials: B
authors.lastname: Le François
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), Ottawa, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Faranak
authors.initials: F
authors.lastname: Vahid-Ansari
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Sean D
authors.initials: SD
authors.lastname: Geddes
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Béïque
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), Ottawa, Canada.
authors.forename: Mireille
authors.initials: M
authors.lastname: Daigle
authors.affiliation: Ottawa Hospital Research Institute (Neuroscience), Ottawa, Canada. palbert@uottawa.ca.|Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, 451 Smyth Road, Ottawa, ON, K1H-8M5, Canada. palbert@uottawa.ca.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Albert
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000222:Adaptation, Physiological; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects; D004268:DNA-Binding Proteins; D003863:Depression / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D007036:Hypothermia, Induced; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D012727:Sex Characteristics; D014157:Transcription Factors / Q000172:deficiency* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C548809:Deaf1 protein, mouse; D014157:Transcription Factors; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin
keywords: Anxiety; Major depression; Raphe; Receptor signaling; Serotonin; Transgenerational