A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.

GWAS研究最近证明了人类的单核苷酸多态性（SNP） 玻璃钢 患有恐惧症的个体的基因。 玻璃钢编码甘氨酸受体（GlyRs）β亚基。鉴定出的SNP位于基因侧翼区域（3'和5'UTR）和内含子区域内。有人认为，这些核苷酸多态性修饰了人类中GlyRs的表达和表型行为，从而导致焦虑表型为轻度高铁状态。过度性抽搐是由于编码GlyRs亚基的基因突变而引起的大规模惊吓表型的人类神经运动疾病。GLRA1 突变比 玻璃钢突变。焦虑表型是否会引起过度上肢神经疾病？在这里，我们比较了两种小鼠模型，它们在鼠中都带有突变Glra1 要么 rb关于焦虑和惊吓表型的基因。纯合子痉挛性的 动物携带 Glra1点突变（从丙氨酸52到丝氨酸）显示异常增强的惊吓反应。此外，痉挛性的 即使在中性背景下，小鼠在惊吓范例中表现出与恐惧相关的行为（冻结，抚养和背脊时间）也有显着变化。 痉挛的 小鼠表现出全长GlyRsβ亚基的表达水平降低，这是由于它们的异常剪接。 rb基因。杂合动物看起来正常，没有明显的行为表型，因此可能反映了GWAS研究中关于恐惧症和惊吓的人类情况。与之相反痉挛性的 小鼠，杂合子 痉挛的动物在中性以及调节条件下均未发现惊吓表型。可能存在其他机制，例如对恐惧和与恐惧相关的行为很重要的神经元网络中甘氨酸能循环中GlyRsβ亚基的调节功能。可能在人类中，由于基因与基因的相互作用（例如，与GLRA1 基因或表观遗传因素是产生恐惧症，特别是惊吓表型所必需的。