Anxiety and Startle Phenotypes inGlrb SpasticandGlra1 SpasmodicMouse Mutants

A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the humanGLRBgene of individuals with a prevalence for agoraphobia.GLRBencodes the glycine receptor (GlyRs) beta 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.GLRA1mutations have been more commonly observed thanGLRBmutations. 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 murineGlra1orGlrbgene with regard to anxiety and startle phenotypes. Homozygousspasmodicanimals carrying aGlra1point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover,spasmodicmice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context.Spasticmice exhibit reduced expression levels of the full-length GlyRs beta subunit due to aberrant splicing of theGlrbgene. 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 tospasmodicmice, heterozygousspasticanimals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs beta 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., withGLRA1genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.