title: A MusD retrotransposon insertion in the mouse Slc6a5 gene causes alterations in neuromuscular junction maturation and behavioral phenotypes.
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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Laurent P
authors.initials: LP
authors.lastname: Bogdanik
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.forename: Kathy E
authors.initials: KE
authors.lastname: Miers
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
mesh_terms: D000818:Animals; D001007:Anxiety; D015153:Blotting, Western; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D006120:Grooming; D006801:Humans; D008297:Male; D018782:Maze Learning; D051379:Mice; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009043:Motor Activity; D016254:Mutagenesis, Insertional; D009154:Mutation; D009433:Neural Inhibition / Q000235:genetics / Q000502:physiology; D009469:Neuromuscular Junction / Q000235:genetics / Q000502:physiology*; D011597:Psychomotor Performance / Q000502:physiology*; D018626:Retroelements / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; D018626:Retroelements; C493270:Slc6a5 protein, mouse