Dataset Information

Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants.

ABSTRACT: 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) ? 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 ? 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 ? 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.

SUBMITTER: Schaefer N

PROVIDER: S-EPMC7433344 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants.

Schaefer Natascha N Signoret-Genest Jérémy J von Collenberg Cora R CR Wachter Britta B Deckert Jürgen J Tovote Philip P Blum Robert R Villmann Carmen C

Frontiers in molecular neuroscience 20200811

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. ...[more]

PMID: 32848605

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Project description:Startle disease is an inherited neurological disorder that causes affected individuals to suffer noise- or touch-induced non-epileptic seizures, excessive muscle stiffness and neonatal apnea episodes. Mutations known to cause startle disease have been identified in glycine receptor subunit (GLRA1 and GLRB) and glycine transporter (SLC6A5) genes, which serve essential functions at glycinergic synapses. Despite the significant successes in identifying startle disease mutations, many idiopathic cases remain unresolved. Exome sequencing in these individuals will identify new candidate genes. To validate these candidate disease genes, zebrafish is an ideal choice due to rapid knockdown strategies, accessible embryonic stages, and stereotyped behaviors. The only existing zebrafish model of startle disease, bandoneon (beo), harbors point mutations in glrbb (one of two zebrafish orthologs of human GLRB) that cause compromised glycinergic transmission and touch-induced bilateral muscle contractions. In order to further develop zebrafish as a model for startle disease, we sought to identify common phenotypic outcomes of knocking down zebrafish orthologs of two known startle disease genes, GLRA1 and GLRB, using splice site-targeted morpholinos. Although both morphants were expected to result in phenotypes similar to the zebrafish beo mutant, our direct comparison demonstrated that while both glra1 and glrbb morphants exhibited embryonic spasticity, only glrbb morphants exhibited bilateral contractions characteristic of beo mutants. Likewise, zebrafish over-expressing a dominant startle disease mutation (GlyR ?1(R271Q)) exhibited spasticity but not bilateral contractions. Since GlyR ?b can interact with GlyR ? subunits 2-4 in addition to GlyR ?1, loss of the GlyR ?b subunit may produce more severe phenotypes by affecting multiple GlyR subtypes. Indeed, immunohistochemistry of glra1 morphants suggests that in zebrafish, alternate GlyR ? subunits can compensate for the loss of the GlyR ?1 subunit. To address the potential for interplay among GlyR subunits during development, we quantified the expression time-course for genes known to be critical to glycinergic synapse function. We found that GlyR ?2, ?3 and ?4a are expressed in the correct temporal pattern and could compensate for the loss of the GlyR ?1 subunit. Based on our findings, future studies that aim to model candidate startle disease genes in zebrafish should include measures of spasticity and synaptic development.

Project description:BackgroundMajor theories propose that perturbed threat learning is central to pathological anxiety, but empirical support is inconsistent. Failures to detect associations with anxiety may reflect limitations in quantifying conditioned responses to anticipated threat, and hinder translation of theory into empirical work. In prior work, we could not detect threat-specific anxiety effects on states of conditioned threat using psychophysiology in a large sample of patients and healthy comparisons. Here, we examine the utility of an alternative fear potentiated startle (FPS) scoring in revealing associations between anxiety and threat conditioning and extinction in this dataset. Secondary analyses further explored associations among conditioned threat responses, subcortical morphometry, and treatment outcomes.MethodsYouths and adults with anxiety disorders and healthy comparisons (n = 306; 178 female participants; 8-50 years) previously completed a well-validated differential threat learning paradigm. FPS and skin conductance response (SCR) quantified psychophysiological responses during threat conditioning and extinction. In this report, we examined normalizing raw FPS scores to intertrial intervals (ITI) to address challenges in more common approaches to FPS scoring which could mask group effects. Secondary analyses examined associations between FPS and subcortical morphometry and with response to exposure-based cognitive behavioral therapy in a subsample of patients.ResultsPatients and comparisons showed comparable differential threat conditioning using FPS and SCR. While SCR suggested comparable extinction between groups, FPS revealed stronger retention of threat contingency during extinction in individuals with anxiety disorders. Extinction indexed with FPS was not associated with age, morphometry, or anxiety treatment outcome.ConclusionITI-normalized FPS may have utility in detecting difficulties in extinguishing conditioned threat responses in anxiety. These findings provide support for extinction theories of anxiety and encourage continued research on aberrant extinction in pathological anxiety.

Dataset Information

Anxiety and Startle Phenotypes in Glrb Spastic and Glra1 Spasmodic Mouse Mutants.

Publications

Anxiety and Startle Phenotypes in <i>Glrb Spastic</i> and <i>Glra1 Spasmodic</i> Mouse Mutants.

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