Hyperekplexia phenotype of glycine receptor alpha1 subunit mutant mice identifies Zn(2+) as an essential endogenous modulator of glycinergic neurotransmission.
Zn(2+) is thought to modulate neurotransmission by affecting currents mediated by ligand-gated ion channels and transmitter reuptake by Na(+)-dependent transporter systems. Here, we examined the in vivo relevance of Zn(2+) neuromodulation by producing knockin mice carrying the mutation D80A in the glycine receptor (GlyR) alpha1 subunit gene (Glra1). This substitution selectively eliminates the potentiating effect of Zn(2+) on GlyR currents. Mice homozygous for Glra1(D80A) develop a severe neuromotor phenotype postnatally that resembles forms of human hyperekplexia (startle disease) caused by mutations in GlyR genes. In spinal neurons and brainstem slices from Glra1(D80A) mice, GlyR expression, synaptic localization, and basal glycinergic transmission were normal; however, potentiation of spontaneous glycinergic currents by Zn(2+) was significantly impaired. Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn(2+) potentiation of alpha1 subunit containing GlyRs, indicating that synaptic Zn(2+) is essential for proper in vivo functioning of glycinergic neurotransmission.
Hirzel
Klaus
K
Abteilung Neurochemie, Max-Planck-Institut für Hirnforschung, Deutschordenstrasse 46, 60528 Frankfurt am Main, Germany.
Müller
Ulrike
U
Latal
A Tobias
AT
Hülsmann
Swen
S
Grudzinska
Joanna
J
Seeliger
Mathias W
MW
Betz
Heinrich
H
Laube
Bodo
B
D000818:Animals; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology; D002460:Cell Line; D002678:Chimera; D004195:Disease Models, Animal; D020821:Dystonic Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004525:Efferent Pathways / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005998:Glycine / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008818:Mice, Neurologic Mutants; D009154:Mutation; D009433:Neural Inhibition / Q000235:genetics; D009924:Organ Culture Techniques; D010641:Phenotype; D018009:Receptors, Glycine / Q000187:drug effects / Q000235:genetics*; D013216:Reflex, Startle / Q000235:genetics*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
C000657604:GLRA1 protein, human; C000657605:Glra1 protein, mouse; D018009:Receptors, Glycine; D015032:Zinc; D005998:Glycine