The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety

Low serotonin(1A) receptor (5-HT1AR) binding is a risk factor for anxiety and depression, and deletion of the 5-HT1AR 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-HT1AR 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-HT1AR 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-HT1AR deficit represents a dual risk for anxiety and that vulnerability to anxiety associated with genetic 5-HT1AR 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.