The serotonin _1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

Abstract

Low serotonin 1A receptor (5-HT 1A R) binding is a risk factor for anxiety and depression, and deletion of the 5-HT 1A R results in anxiety-like behavior in mice. Here we show that anxiety-like behavior in mice also can be caused, independently of the offspring's own 5-HT 1A R genotype, by a receptor deficit in the mother: a nongenetic transmission of a genetic defect. Some of the nongenetically transmitted anxiety manifestations were acquired prenatally and linked to a delay in dentate gyrus maturation in the ventral hippocampus of the offspring. Both the developmental delay and the anxiety-like phenotype were phenocopied by the genetic inactivation of p16 ink4a encoding a cyclin-dependent kinase inhibitor implicated in neuronal precursor differentiation. No maternal 5-HT 1A R genotype-dependent anxiety developed when the strain background was switched from Swiss Webster to C57BL/6, consistent with the increased resilience of this strain to early adverse environment. Instead, all anxiety manifestations were caused by the offspring's own receptor deficiency, indicating that the genetic and nongenetic effects converge to common anxiety manifestations. We propose that 5-HT 1A R deficit represents a dual risk for anxiety and that vulnerability to anxiety associated with genetic 5-HT 1A R deficiency can be transmitted by both genetic and nongenetic mechanisms in a population. Thus, the overall effect of risk alleles can be higher than estimated by traditional genetic assays and may contribute to the relatively high heritability of anxiety and psychiatric disorders in general.genetic risk | heritability | cross-fostering S tudies have identified mutant/polymorphic variants of genes, each with a relatively small contribution to the risk of depression, anxiety, schizophrenia, and other psychiatric diseases. However, demonstrable genetic influences explain only a small fraction of estimated heritability in psychiatric conditions. This "missing heritability" could be caused by a large number of undiscovered alleles or by mechanisms that amplify the effect of risk alleles but are not genetic in nature. We tested the hypothesis that mutant/polymorphic variants can have a larger effect if, besides their purely genetic effect, they have an additional "environmental" effect. For example, gene variants could influence maternal physiology, affecting the developmental program of the offspring, and consequently also increasing the risk for psychopathology. Indeed, adverse prenatal maternal and/or postnatal environment increases vulnerability to various diseases, including psychiatric disorders, in adulthood (1, 2), and one may extrapolate these findings to an abnormal maternal/parental environment related to disease-associated genes/gene variants.One of the few candidate genes whose function has been associated with anxiety and depression encodes the serotonin 1A receptor (5-HT 1A R) (3). Reduced binding or binding potential in the 5-HT 1A R has been linked to posttraumatic stress and panic disorders (3) and depression (4), and a...

Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment

“…Recent studies related to mood and anxiety have indicated that genetic factors may also influence neurodevelopment by altering maternal physiology during pregnancy (Toth, 2014). Interestingly, maternal genotype effects on fetal development have been reported in offspring of 5-HT 1A and TPH1 null mice (Cote et al, 2007;Gleason et al, 2010). Although very useful for understanding these components of the 5-HT system, complete loss of these critical proteins does not occur in the human population.…”

“…Emerging evidence points to maternal genotype as a potential contributor to offspring risk of neurodevelopmental phenotypes. For example, the prenatal impact of maternal genotype in 5-HT 1A receptor null mice confers life-long anxiety-like behavior in offspring, independent of offspring genotype (Gleason et al, 2010). This possibility has recently been explored in ASD, with risk increased in the offspring of mothers with the high-expressing SLC6A4 5-HTTLPR long allele (Kistner-Griffin et al, 2011).…”

Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects

“…44 Although further improvements are required, the intranasal route offers a first potential way for C-1A-siRNA delivery to brain. This route allowed the same effects than the i.c.v.…”

The effects of serotonin1A receptor on female mice body weight and food intake are associated with the differential expression of hypothalamic neuropeptides and the GABAA receptor

“…Both C57BL Wild type (WT) and C57BL 5-HT 1A -R (À/À) (KO) female mice were used in this study (Bailey and Toth, 2004;Gleason et al, 2010;Parks et al, 1998;Sarnyai et al, 2000). Mice were acquired, cared for and handled in conformity with the U.S. Public Health Service's ''Guide for the Care and Use of Laboratory Animals''.…”