Research Report 2010 - MDC

A B CD E FRNA editing emerges as a compensatory albeitpathophysiological mechanism in hyperexcitabilitydisordersTonic inhibition of neuron firing plays a pivotal role inbrain information transfer because it provides a globalcontrol of neuronal excitability. A large body of evidencehas implicated impaired hippocampal GABAergic inhibitionin enhanced susceptibility of neurons to becomehyperexcitable and to generate epileptiform discharges.Glycine receptors have recently been involvedin hippocampal tonic inhibition, and we could isolatemRNAs encoding gain-of-function glycine receptorswith substantially increased apparent affinities forglycine (Figure A-C) and taurine, rendering them perfectlyadjusted to mediating tonic inhibition. We couldestablish that high affinity glycine receptors arise frompost-transcriptional C-to-U RNA editing (Figure D), asdemonstrated by the absence of encoding genomicsequences (Figure E). Furthermore, the C-to-U RNA editinginhibitor zebularine was found to be effective ontonic glycinergic currents elicited in hippocampal neurons(Figure F). Having these tools at hand, functionalanalysis is carried out at a cellular level of investigation,using high affinity receptor expression in primary hippocampalneurons, and at a systemic level, using highaffinity receptor screening of resected hippocampifrom mesial temporal lobe epilepsy (TLE) patients. Sofar, our data point to a compensatory and homeostatic,but pathophysiological, role of high affinity glycinereceptor activation in the course of TLE. Therefore, weare interested in developing this novel functionalglycine receptor property into novel pharmacologicalapproaches to the treatment of hyperexcitability disorders.Selected PublicationsLegendre, P, Förstera, B, Jüttner, R, Meier, JC. (2009). Glycine receptorscaught between genome and proteome – Functional implications ofRNA editing and splicing. Front. Mol. Neurosci. 2:23.Eichler, SA, Förstera, B, Smolinsky, B, Jüttner, R, Lehmann, T-N, Fähling, M,Schwarz, G, Legendre P, Meier, JC. (2009). Splice-specific roles of glycinereceptor α3 in the hippocampus. Eur. J. Neurosci. 30, 1077-1091.Eichler, SA, Kirischuk, S, Jüttner, R, Schäfermeier, PK, Legendre, P, Lehmann,T-N, Gloveli, T, Grantyn, R, Meier, JC. (2008). Glycinergic tonic inhibition ofhippocampal neurons with depolarizing GABAergic transmission elicitshistopathological signs of temporal lobe epilepsy. J. Cell. Mol. Med.12,2848-2866.Smolinsky, B, Eichler, SA, Buchmeier, S, Meier, JC*, Schwarz, G*. (2008).Splice-specific functions of gephyrin in molybdenum cofactorbiosynthesis. J. Biol. Chem. 283,17370-17379. * Equal contribution.Meier, JC, Henneberger, C, Melnick, I, Racca, C, Harvey, RJ, Heinemann, U,Schmieden V, Grantyn, R. (2005). RNA editing produces P185L amino acidsubstitution in glycine receptor α3 resulting in high agonist potency.Nature Neurosci. 8,736-744.Function and Dysfunction of the Nervous System 169