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Abstract
Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the α (spasmodic, oscillator, cincinnati, Nmf11) or the β (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABAA receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.
Highlights
Synaptic inhibition is mediated by activation of glycine receptors (GlyRs) and γ-aminobutyric acid (GABA) receptors
Why do some mutations in the GlyR genes (Glra1 or Glrb) in rodents result in a mild and others in a lethal phenotype? Are there differences in compensatory mechanisms? The strength of a phenotype could result from mouse line background as recently shown for the two hit splice mutation in the mouse mutant spastic
Mice carrying human mutations showed an onset of symptoms as massive tremor and startle attacks with the age of 15 days when developmental changes in GlyR subunit composition are almost completed
Summary
Synaptic inhibition is mediated by activation of glycine receptors (GlyRs) and γ-aminobutyric acid (GABA) receptors. This exon duplication in Glra1 transcript results in a frameshift mutation with a novel generated premature stop codon (F159X) followed by a loss of GlyRα1 function comparable to the oscillator mutant. Occuring mutations of the murine GlyRα1 subunit, as in the spontaneous mouse mutant oscillator, lead to loss of the respective protein, resembling the knock-out α1 situation (Kling et al, 1997).
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