Hyperekplexia phenotype of glycine receptor α1 subunit mutant mice identifies Zn2+ as an essential endogenous modulator of glycinergic neurotransmission

Zn2+ 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 Zn2+ neuromodulation by producing knockin mice carrying the mutation D80A in the glycine receptor (GlyR) alpha 1 subunit gene (Glra1). This substitution selectively eliminates the potentiating effect of Zn2+ 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 Zn2+ was significantly impaired. Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn2+ potentiation of alpha 1 subunit containing GlyRs, indicating that synaptic Zn2+ is essential for proper in vivo functioning of glycinergic neurotransmission.