%0 Journal Article %A Geoffrey S. Findlay %A Rachel Phelan %A Michael T. Roberts %A Gregg E. Homanics %A Susan E. Bergeson %A Gregory F. Lopreato %A S. John Mihic %A Yuri A. Blednov %A R. Adron Harris %T Glycine Receptor Knock-In Mice and Hyperekplexia-Like Phenotypes: Comparisons with the Null Mutant %D 2003 %R 10.1523/JNEUROSCI.23-22-08051.2003 %J The Journal of Neuroscience %P 8051-8059 %V 23 %N 22 %X Strychnine-sensitive glycine receptors (GlyRs) inhibit neurotransmission in the spinal cord and brainstem. To better define the function of this receptor in vivo, we constructed a point mutation that impairs receptor function in the α1-subunit and compared these knock-in mice to oscillator (spdot) mice lacking functional GlyR α1-subunits. Mutation of the serine residue at amino acid 267 to glutamine (α1S267Q) results in a GlyR with normal glycine potency but decreased maximal currents, as shown by electrophysiological recordings using Xenopus oocytes. In addition, single-channel recordings using human embryonic kidney 293 cells indicated profoundly altered properties of the mutated GlyR. We produced knock-in mice bearing the GlyR α1 S267Q mutation to assess the in vivo consequences of selectively decreasing GlyR efficacy. Chloride uptake into brain synaptoneurosomes from knock-in mice revealed decreased responses to maximally effective glycine concentrations, although wild-type levels of GlyR expression were observed using 3H-strychnine binding and immunoblotting. A profound increase in the acoustic startle response was observed in knock-in mice as well as a “limb clenching” phenotype. In contrast, no changes in coordination or pain perception were observed using the rotarod or hot-plate tests, and there was no change in GABAA-receptor-mediated chloride uptake. Homozygous S267Q knock-in mice, like homozygous spdot mice, exhibited seizures and died within 3 weeks of birth. In heterozygous spdot mice, both decreased 3H-strychnine binding and chloride flux were observed; however, neither enhanced acoustic startle responses nor limb clenching were seen. These data demonstrate that a dominant-negative point mutation in GlyR disrupting normal function can produce a more dramatic phenotype than the corresponding recessive null mutation, and provides a new animal model to evaluate GlyR function in vivo. %U https://www.jneurosci.org/content/jneuro/23/22/8051.full.pdf