Regulation of Serotonin 1A Receptor SUMOylation by SENP2 and PIASxα

Serotonin 1A receptors (5-HT1ARs) are implicated in the control of mood, cognition, and memory and in various neuropsychiatric disorders such as depression and anxiety. As such, understanding the regulation of 5-HT1ARs will inform the development of better treatment approaches. We previously demonstrated 5-HT1ARs are SUMOylated by SUMO1 in the rat brain. Agonist stimulation increased SUMOylation and was further enhanced when combined with 17β-estradiol-3-benzoate (EB), which are treatments that cause the transient and prolonged desensitization of 5-HT1AR signaling, respectively. In the current study, we identified the protein inhibitor of activated STAT (PIAS)xα as the enzyme that facilitates SUMOylation, and SENP2 as the protein that catalyzes the deSUMOylation of 5-HT1ARs. We demonstrated that PIASxα significantly increased in the membrane fraction of rats co-treated with EB and an agonist, compared to either the EB-treated or vehicle-treated groups. The acute treatment with an agonist alone shifted the location of SENP2 from the membrane to the cytoplasmic fraction, but it has little effect on PIASxα. Hence, two separate mechanisms regulate SUMOylation and the activity of 5-HT1ARs by an agonist and EB. The effects of EB on 5-HT1AR SUMOylation and signaling may be related to the higher incidence of mood disorders in women during times with large fluctuations in estrogens. Targeting the SUMOylation of 5-HT1ARs could have important clinical relevance for the therapy for several neuropsychiatric disorders in which 5-HT1ARs are implicated.

Personality, subjective well-being, and the serotonin 1a receptor gene in common marmosets (Callithrix jacchus)

Studies of personality traits in common marmosets (Callithrix jacchus) indicate that there are five or six constructs—Sociability, Dominance, Neuroticism, Openness, and two related to Conscientiousness. The present study attempted to determine whether our earlier study of laboratory-housed individuals only yielded three—Dominance, Sociability, and Neuroticism—because of a low amount of between-subjects variance. To do so, we increased our sample size from 77 to 128. In addition, we ascertained the reliability and validity of ratings and whether polymorphisms related to the serotonin 1a receptor were associated with personality. We found Sociability, Dominance, and Negative Affect factors that resembled three domains found in previous studies, including ours. We also found an Openness and Impulsiveness factor, the latter of which bore some resemblance to Conscientiousness, and two higher-order factors, Pro-sociality and Boldness. In further analyses, we could not exclude the possibility that Pro-sociality and Boldness represented a higher-level of personality organization. Correlations between personality factors and well-being were consistent with the definitions of the factors. There were no significant associations between personality and genotype. These results suggest that common marmoset personality structure varies as a function of rearing or housing variables that have not yet been investigated systematically.

Does human serotonin-1A receptor polymorphism (rs6295) code for pain and associated symptoms in fibromyalgia syndrome?

Genetic predisposition may play an important role in the development of fibromyalgia syndrome (FMS). Serotonin is known to be involved in pain modulation and serotonin-1A receptor plays a considerable role in determining the central 5-HT tone. Consequently, variation in 5-HT1A receptor gene (HTR1A) may be responsible for inter-individual variability in pain sensitivity and other clinical symptoms of FMS. Therefore, the objectives of this research work were to study the gene polymorphism of 5-HTR1A gene and to explore the correlation between rs6295 genotype (−1019C/G HTR1A) and duration of pain, pain intensity and pain related depression and anxiety, if any, in FMS. 5-HTR1A genotype for the C(-1019)G polymorphism was typed in 62 patients with FMS and 42 healthy subjects. Present pain intensity, components of pain and pain related depression and anxiety were assessed using the numerical pain rating scale, McGill pain questionnaire and Hamilton depression and anxiety rating scale respectively. 5-HTR1A gene was represented by three different genotypes, homozygous C/C, heterozygous C/G and homozygous G/G. Analysis of the 5-HTR1A gene showed a frequency of 58%, 31% and 11% for the C/C, C/G and G/G genotypes, respectively in FMS group. This proportion was 69%, 23% and 8% in healthy subjects. No significant correlation was observed between 5-HTR1A gene polymorphism and pain and related symptoms in FMS patients. To the best of our knowledge this is the first study which investigated the correlation between the 5-HTR1A gene polymorphism and pain intensity, the affective component of pain, pain related depression and anxiety in FMS.

Ventral prefrontal serotonin 1A receptor binding: neural marker of resilience in individuals with high familial risk for mood disorder and suicidal behavior?

BACKGROUND: Mood disorders and suicidality have moderate heritability and are associated with altered corticolimbic serotonin 1A receptor (5-HT1A) binding potential. However, it is unclear whether these alterations reflect heritable risk or resilience markers, compensatory mechanisms, or illness-related changes as 5-HT1A binding has never been reported in unaffected high risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset. METHODS: PET imaging quantified brain 5-HT1A binding potential BPND using [11C]CUMI-101 in healthy volunteers (HV) and three groups with one or more relatives with early-onset mood disorder and suicide attempt: 1. HR individuals; 2. HR individuals with a lifetime mood disorder (HR-MOOD); and 3. HR-MOOD individuals with lifetime history of suicide attempt (HR-MOOD/SA). Two additional studies included HV, individuals with low familial risk and current mood disorder (MOOD) and MOOD with lifetime suicide attempt (MOOD/SA) to identify differences persisting across independent cohorts (total N=185: 59 HV, 23 HR, 64 HR-MOOD or MOOD, and 39 HR-MOOD/SA or MOOD/SA). Univariate analysis tested for regional differences and multivoxel pattern analysis (MVPA) tested whether 5-HT1A BPND could distinguish HV, HR, HR-MOOD and HR-MOOD/SA. RESULTS: Low ventral prefrontal 5-HT1A BPND in lifetime MOOD/SA vs. HV and HR was consistently observed across study populations. MVPA distinguished HV from HR-MOOD/SA with informative regions in ventral prefrontal and temporal cortex (peak out-of-sample area under the ROC curve=0.74, p<0.001 corrected). MOOD alone groups did not consistently differ from HV groups. CONCLUSIONS: Low ventral prefrontal 5-HT1A BPND may reflect suicide-related pathology. Further studies are needed to determine if higher ventral prefrontal 5-HT1A BPND may confer resilience for developing suicidal behavior in the context of mood disorders. If so, it could be a potential suicide prevention target.