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The Journal of Neuroscience, April 1, 2002, 22(7):2505-2512

Disease-Specific Human Glycine Receptor ₁ Subunit Causes Hyperekplexia Phenotype and Impaired Glycine- and GABA_A-Receptor Transmission in Transgenic Mice

Lore Becker^{1, 2}, Jörg von Wegerer³, Johannes Schenkel², Hanns-Ulrich Zeilhofer⁴, Dieter Swandulla³, and Hans Weiher¹

¹ Institut für Diabetesforschung, 80804 Munich, Germany, ² Forschungszentrum Karlsruhe, Institut für Toxikologie und Genetik, 76021 Karlsruhe, Germany, ³ Institut für Physiologie, Universität Bonn, 53111 Bonn, Germany, and ⁴ Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen, 91054 Erlangen, Germany

Hereditary hyperekplexia is caused by disinhibition of motoneurons resulting from mutations in the ionotropic receptor for the inhibitory neurotransmitter glycine (GlyR). To study the pathomechanisms involved in vivo, we generated and analyzed transgenic mice expressing the hyperekplexia-specific dominant mutant human GlyR ₁ subunit 271Q. Tg271Q transgenic mice, in contrast to transgenic animals expressing a wild-type human ₁ subunit (tg271R), display a dramatic phenotype similar to spontaneous and engineered mouse mutations expressing reduced levels of GlyR. Electrophysiological analysis in the ventral horn of the spinal cord of tg271Q mice revealed a diminished GlyR transmission. Intriguingly, an even larger reduction was found for GABA_A-receptor-mediated inhibitory transmission, indicating that the expression of this disease gene not only affects the glycinergic system but also leads to a drastic downregulation of the entire postsynaptic inhibition. Therefore, the transgenic mice generated here provide a new animal model of systemic receptor interaction to study inherited and acquired neuromotor deficiencies at different functional levels and to develop novel therapeutic concepts for these diseases.

Key words: hyperekplexia; transgenic mouse model; neuromotor phenotype; glycine receptor; GABA_A receptor; impaired postsynaptic inhibition

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272505-08$05.00/0

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