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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0254-y) contains supplementary material, which is available to authorized users.

Genetic, epigenetic and posttranscriptional mechanisms for treatment of major depression: the 5-HT1A receptor gene as a paradigm

“…39 However, the DEAF1 knockout mice showed a sex-and test-dependent anxiety phenotype that was more pronounced in males. 104 However, the phenotype was very mild, likely due to a desensitization of G-protein coupling to potassium channels. 104 Specific, inducible knockdown in adult male mice of 5-HT 1A autoreceptors by 30% resulted in a stress-resilience phenotype with enhanced and more rapid response to SSRI treatment.…”

“…104 However, the phenotype was very mild, likely due to a desensitization of G-protein coupling to potassium channels. 104 Specific, inducible knockdown in adult male mice of 5-HT 1A autoreceptors by 30% resulted in a stress-resilience phenotype with enhanced and more rapid response to SSRI treatment. 105 Similarly, acute small interfering RNA (siRNA)-induced knockdown of 5-HT 1A autoreceptors in male mice induced a rapid antidepressant-like phenotype within days 106 and enhanced response to SSRIs.…”

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior

“…These findings implicate a key role for the endogenous repressor Freud-1 in 5-HT1A autoreceptor expression leading to reduced raphe 5-HT and antidepressant-resistant anxiety and depression. In contrast, global knockout of the repressor Deaf1 resulted in up-regulation of 5-HT1A autoreceptor expression, reduced raphe 5-HT, but only a mild anxiety phenotype (Czesak et al, 2012;Luckhart et al, 2016), consistent with a stronger effect of Freud-1 to repress the human 5-HT1A gene in raphe cells Ou et al, 2003).…”

“…Brains were cryo-sectioned at a thickness of 25 μm and mounted sections were maintained at −80°C until processing. Mounted sections were processed for 125 I-MPPI (Perkin Elmer, Boston, MA) autoradiography as described (Donaldson et al, 2014;Luckhart et al, 2016). Sections were exposed to Kodak BioMax MR film (VWR) for 24 h. Films were digitized at 1200-dpi resolution using an Epson Perfection V500 Photo Scanner, and signal density was measured using the mean luminosity function in ImageJ (1.49).…”

The adaptive brain in mental health: overcoming inherited risk factors

“…17,18 In Deaf1 knockout mice, despite similar alterations in 5-HT1A expression, adaptations in the signalling of 5-HT1A receptors across generations led to the development of a mild behavioural phenotype. 19 Thus, transgenerational molecular adaptation involving changes in gene expression appears to reduce the impact of genetic and nongenetic changes in the HTR1A gene with succeeding generations. By contrast, a mouse model of unpredictable maternal stress and separation from offspring leads to transgenerational transmission across 3 generations of a behavioural phenotype, including impaired social interaction and cognition and increased stress resilience, with persistent changes in pre-and postsynaptic 5-HT1A receptor activity and circuitry.…”