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The Journal of Neuroscience, September 3, 2003, 23(22):8051-8059

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Glycine Receptor Knock-In Mice and Hyperekplexia-Like Phenotypes: Comparisons with the Null Mutant

Geoffrey S. Findlay,¹ Rachel Phelan,¹ Michael T. Roberts,¹ Gregg E. Homanics,² Susan E. Bergeson,¹ Gregory F. Lopreato,¹ S. John Mihic,¹ Yuri A. Blednov,¹ and R. Adron Harris¹

¹Waggoner Center for Alcohol and Addiction Research, Section of Neurobiology, University of Texas at Austin, Austin, Texas 78712, and ²Departments of Anesthesiology and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

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 ₁-subunit and compared these knock-in mice to oscillator (spd^ot) mice lacking functional GlyR ₁-subunits. Mutation of the serine residue at amino acid 267 to glutamine (₁S267Q) 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 ₁ 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 GABA_A-receptor-mediated chloride uptake. Homozygous S267Q knock-in mice, like homozygous spd^ot mice, exhibited seizures and died within 3 weeks of birth. In heterozygous spd^ot 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.

Key words: GlyR; knock-in; oscillator; spd-ot; mice; channel gating; glycine; hyperekplexia; strychnine; chloride flux; Xenopus oocytes; acoustic startle response

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Received Feb 13, 2003; revised July 8, 2003; accepted July 17, 2003.

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