Abstract
Glycine is the major inhibitory neurotransmitter in the spinal cord and some brain regions. The presynaptic glycine transporter, GlyT2, is required for sustained glycinergic transmission through presynaptic reuptake and recycling of glycine. Mutations in SLC6A5, encoding GlyT2, cause hereditary hyperekplexia in humans, and similar phenotypes in knock-out mice, and variants are associated with schizophrenia. We identified a spontaneous mutation in mouse Slc6a5, caused by a MusD retrotransposon insertion. The GlyT2 protein is undetectable in homozygous mutants, indicating a null allele. Homozygous mutant mice are normal at birth, but develop handling-induced spasms at five days of age, and only survive for two weeks, but allow the study of early activity-regulated developmental processes. At the neuromuscular junction, synapse elimination and the switch from embryonic to adult acetylcholine receptor subunits are hastened, consistent with a presumed increase in motor neuron activity, and transcription of acetylcholine receptors is elevated. Heterozygous mice, which show no reduction in lifespan but nonetheless have reduced levels of GlyT2, have a normal thermal sensitivity with the hot-plate test, but differences in repetitive grooming and decreased sleep time with home-cage monitoring. Open-field and elevated plus-maze tests did not detect anxiety-like behaviors; however, the latter showed a hyperactivity phenotype. Importantly, grooming and hyperactivity are observed in mouse schizophrenia models. Thus, mutations in Slc6a5 show changes in neuromuscular junction development as homozygotes, and behavioral phenotypes as heterozygotes, indicating their usefulness for studies related to glycinergic dysfunction.
Highlights
In the mammalian nervous system, inhibitory synaptic transmission is primarily mediated by vesicular release of gammaaminobutyric acid (GABA) and glycine
Of all the genes documented by the Mouse Genome Informatics website in this region, Slc6a5, encoding GlyT2, at 57.2 Mb on the Chromosome 7 (Fig. 1.D), was selected for closer analysis because of the similarity of the phenotypes of the new mutant and the published Slc6a5 knockout allele [23]
We investigated the effects of this overactivity on two postnatal developmental features of the NMJ that had not been previously examined in the Slc6a5 knockout mice: synapse elimination, and the molecular switch of the acetylcholine receptor subunit expression from the embryonic gamma subunit to the adult epsilon subunit
Summary
In the mammalian nervous system, inhibitory synaptic transmission is primarily mediated by vesicular release of gammaaminobutyric acid (GABA) and glycine. GABAergic neurons predominate in the forebrain, while glycinergic neurons are primarily found in the brain stem and the spinal cord. Motoneurons receive inhibitory connections from Renshaw cells, propriospinal interneurons, and brain stem projections [1,2]. Renshaw cells are activated by axon collaterals of motoneurons innervating proximal muscles, and form a feedback loop onto the activating motoneuron or synergistic motoneurons (recurrent inhibition) [3,4,5,6]. Propriospinal interneurons relay inputs from the muscles or joints, and can connect directly, or via other spinal interneurons, to the motoneurons. Descending inputs from the ventromedial medulla contribute GABA/ glycinergic inhibition on the motoneurons [7]. Direct or indirect glycinergic inhibition onto spinal motoneurons modulates their excitability, and voluntary movements, central pattern generators responsible for locomotion and breathing, the strength of muscle contractions, and muscle relaxation
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