Abstract
Startle disease or hereditary hyperekplexia has been shown to result from mutations in the α1-subunit gene of the inhibitory glycine receptor (GlyR). In hyperekplexia patients, neuromotor symptoms generally become apparent at birth, improve with age, and often disappear in adulthood. Loss-of-function mutations of GlyR α or β-subunits in mice show rather severe neuromotor phenotypes. Here, we generated mutant mice with a transient neuromotor deficiency by introducing a GlyR β transgene into the spastic mouse (spa/spa), a recessive mutant carrying a transposon insertion within the GlyR β-subunit gene. In spa/spa TG456 mice, one of three strains generated with this construct, which expressed very low levels of GlyR β transgene-dependent mRNA and protein, the spastic phenotype was found to depend upon the transgene copy number. Notably, mice carrying two copies of the transgene showed an age-dependent sensitivity to tremor induction, which peaked at ∼ 3–4 weeks postnatally. This closely resembles the development of symptoms in human hyperekplexia patients, where motor coordination significantly improves after adolescence. The spa/spa TG456 line thus may serve as an animal model of human startle disease.
Highlights
Distinct hereditary neuromotor disorders have been shown to be due to disinhibition of motoneurons resulting from mutations in the receptor for the inhibitory amino acid neurotransmitter glycine (GlyR)
In spa/spa TG456 mice, one of three strains generated with this construct, which expressed very low levels of glycine receptor (GlyR) b transgene-dependent mRNA and protein, the spastic phenotype was found to depend upon the transgene copy number
We have reported that the spa/spa phenotype can be rescued by transgenic expression of an exogenous rat GlyR b minigene (Hartenstein et al, 1996)
Summary
Distinct hereditary neuromotor disorders have been shown to be due to disinhibition of motoneurons resulting from mutations in the receptor for the inhibitory amino acid neurotransmitter glycine (GlyR). Amino acid substitutions in the ligand binding a1-subunit of the GlyR have been identi®ed in both genetically recessive and dominant forms of hereditary hyperekplexia or startle syndrome (Shiang et al, 1993; Rees et al, 1994). This disease is characterized by startle-induced, generalized muscle contractions, which are often accompanied with hypertonia. The disease phenotype correlates well with the functional role and the anatomical localization of the GlyR, the major inhibitory ligandgated chloride channel in the spinal cord and brain stem. During development and in other brain regions, additional differentially expressed a-subunit isoforms (a2±a4) create GlyR diversity (Grenningloh et al, 1990a; Kuhse et al, 1990; Malosio et al, 1991; Betz, 1992; Matzenbach et al, 1994)
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