Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

Abstract

Normal aging of the brain differs from pathological conditions and is associated with increased risk for psychiatric and neurological disorders. In addition to its role in the etiology and treatment of mood disorders, altered serotonin (5-HT) signaling is considered a contributing factor to aging; however, no causative role has been identified in aging. We hypothesized that a deregulation of the 5-HT system would reveal its contribution to agerelated processes and investigated behavioral and molecular changes throughout adult life in mice lacking the regulatory presynaptic 5-HT 1B receptor (5-HT 1B R), a candidate gene for 5-HTmediated age-related functions. We show that the lack of 5-HT 1B R (Htr1b KO mice) induced an early age-related motor decline and resulted in decreased longevity. Analysis of life-long transcriptome changes revealed an early and global shift of the gene expression signature of aging in the brain of Htr1b KO mice. Moreover, molecular changes reached an apparent maximum effect at 18-months in Htr1b KO mice, corresponding to the onset of early death in that group. A comparative analysis with our previous characterization of aging in the human brain revealed a phylogenetic conservation of age-effect from mice to humans, and confirmed the early onset of molecular aging in Htr1b KO mice. Potential mechanisms appear independent of known central mechanisms (Bdnf, inflammation), but may include interactions with previously identified age-related systems (IGF-1, sirtuins). In summary, our findings suggest that the onset of age-related events can be influenced by altered 5-HT function, thus identifying 5-HT as a modulator of brain aging, and suggesting age-related consequences to chronic manipulation of 5-HT.

Corticolimbic Transcriptome Changes are State-Dependent and Region-Specific in a Rodent Model of Depression and of Antidepressant Reversal

“…As the analytical goal was to use profiles of expression over large groups of genes as an 'experimental assay' to measure UCMS and drug effects, thresholds for gene selection were kept at moderate stringencies for group comparisons (Po0.05 and changes greater than 20%; see Materials and methods and Discussion). We have previously demonstrated the validity of this approach at characterizing robust and significant biological events in brain tissue (Sibille et al, 2007). Accordingly, the levels of 254 gene transcripts were significantly affected by UCMS in CC, 299 in AMY, and 166 in DG (Figure 3; Supplementary Tables S1-S3).…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…5-HT1B-R knockout mice do not exhibit any clear change in anxiety-like behavior. However, these mice do show an exaggerated autonomic reaction to acute stress and depressive-like enhancement of paradoxical sleep and an antidepressant-like response in forced swim and tail suspension test that is normalized by SRI treatment or PCPA depletion of central serotonin (Boutrel et al, 1999;Brunner et al, 1999;de Boer and Koolhaas, 2005;Dirks et al, 2001;Groenink et al, 2003;Jones and Lucki, 2005;Lopez-Rubalcava et al, 2000;Mayorga et al, 2001;Olivier and van Oorschot, 2005;Pattij et al, 2003;Ramboz et al, 1996;Sibille et al, 2007). On the face of it the antidepressant-like phenotype is congruent with the antidepressant-like activity of the selective 5-HT1B-R antagonist SB-616234-A .…”

Ageing abolishes the effects of fluoxetine on neurogenesis

“…48 The correlation between ageing and serotonin signaling has also been substantiated by the premature ageing of brains from animals bearing a targeted disruption of the serotonin receptor 1b. 49 One might speculate about the existence of intrinsic differences in differentiation and survival capacities of newly generated neurons in aged brains as compared to young brains. However, some observations argue against this hypothesis.…”