The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety
The serotonin1A receptor gene as a genetic and prenatal maternal environmental factor in anxiety
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DOI：
10.1073/pnas.0914805107
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发表时间：
2010-04-20
影响因子：
11.1
通讯作者：
Toth, M.
中科院分区：
文献类型：
--
作者：
Gleason, G.;Liu, B.;Toth, M.
低血清素（1A）受体（5-HT 1AR）结合是焦虑和抑郁的危险因素，5-HT 1AR的缺失导致小鼠的焦虑样行为。在这里，我们表明，小鼠的焦虑样行为也可以引起，独立于后代自己的5-HT 1AR基因型，在母亲的受体缺陷：遗传缺陷的非遗传传递。一些非遗传传递的焦虑表现是在产前获得的，并与后代腹侧海马齿状回成熟延迟有关。发育迟缓和焦虑样表型都是通过p16（ink 4a）的遗传失活来表现的，p16编码一种与神经元前体分化有关的细胞周期蛋白依赖性激酶抑制剂。当菌株背景从Swiss韦伯斯特转换为C57 BL/6时，没有发生母体5-HT 1AR基因型依赖性焦虑，这与该菌株对早期不利环境的恢复力增加一致。相反，所有的焦虑表现都是由后代自身的受体缺陷引起的，这表明遗传和非遗传效应会导致常见的焦虑表现。我们认为，5-HT 1AR缺陷是焦虑的双重风险，与遗传性5-HT 1AR缺陷相关的焦虑易感性可以通过遗传和非遗传机制在人群中传播。因此，风险等位基因的总体影响可能高于传统遗传测定的估计，并可能导致焦虑和精神疾病的遗传性相对较高。
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.