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 alpha1 subunit 271Q. Tg271Q transgenic mice, in contrast to transgenic animals expressing a wild-type human alpha1 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.

Actions of the new antiepileptic drug lamotrigine (LTG) were characterized using extracellular and whole cell patch clamp recordings from rat CA1 and CA3 pyramidal cells in vitro. The results suggest that LTG, beside its previously described effect on the fast sodium inward current, also modulates – presumably voltage-gated – calcium currents and the transient potassium outward current I_D. These may be effective mechanisms to inhibit pathological excitation in epilepsy and may be of potential benefit in treating underlying cellular disturbances in bipolar disorder.

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The learning and memory of Drosophila melanogaster strains carrying the Su-var(3)6(01) mutation, which is known to affect the structural gene of a protein phosphatase 1 isoenzyme, PP1(87B), were studied in various behavioral paradigms. Three lines of Drosophila comprising the Su-var(3)6(01) mutation in different genetic backgrounds were shown to have diminished protein phosphatase 1 activity and behavioral anomalies. Associative olfactory learning and visual conditioning were impaired. Olfactory acuity for the odorants used and response to electric shock were largely unchanged in the mutant lines. The motility and flight activity of the mutants were reduced. Habituation of the landing response, a nonassociative learning process, was more pronounced in heterozygotes of the mutants than in the wild-type control strains. Taken together with earlier data, the results indicate that protein phosphatase PP1(87B), while affecting several cellular processes, is also part of the biochemical machinery of various forms of neuromodulation in Drosophila.