Hyperekplexia Phenotype of Glycine Receptor α1 Subunit Mutant Mice Identifies Zn2+ as an Essential Endogenous Modulator of Glycinergic Neurotransmission

• DOI: 10.1016/j.neuron.2006.09.035
• Publication Date: 2006-11-27T14:57:23Z
• Authors: Klaus Hirzel; Ulrike Müller; A. Tobias Latal; Swen Hülsmann; Joanna Grudzinska; Mathias W. Seeliger; Heinrich Betz; Bodo Laube
• Keywords: Male; 0301 basic medicine; Neuroscience(all); HUMDISEASE; Glycine; Efferent Pathways; MOLNEURO; Cell Line; Mice; Mice, Neurologic Mutants; 03 medical and health sciences; Organ Culture Techniques; Receptors, Glycine; Animals; Humans; 0303 health sciences; Chimera; Neural Inhibition; Mice, Mutant Strains; Mice, Inbred C57BL; Disease Models, Animal; Phenotype; SIGNALING; Dystonic Disorders; Mutation; Female; Brain Stem

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.