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The Journal of Neuroscience, June 1, 2003, 23(11):4700-4711

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Deformation of Network Connectivity in the Inferior Olive of Connexin 36-Deficient Mice Is Compensated by Morphological and Electrophysiological Changes at the Single Neuron Level

Chris I. De Zeeuw,¹ Edilzh Chorev,² Anna Devor,² Yait Manor,³ Ruben S. Van Der Giessen,¹ Marcel T. De Jeu,¹ Casper C. Hoogenraad,¹ Jan Bijman,¹ Tom J. H. Ruigrok,¹ Pim French,¹ Dick Jaarsma,¹ Werner M. Kistler,¹ Carola Meier,⁴ Elisabeth Petrasch-Parwez,⁴ Rolf Dermietzel,⁴ Goran Sohl,⁵ Martin Gueldenagel,⁴ Klaus Willecke,⁵ and Yosi Yarom²

¹ Department of Neuroscience, Medical Faculty, Erasmus MC, 3000DR Rotterdam, The Netherlands, ² Department of Neurobiology, Institute of Life Sciences, Hebrew University, Jerusalem 91904, Israel, ³ Department of Life Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva 84105, Israel, ⁴ Department of Neuroanatomy and Molecular Brain Research, Institute of Anatomy, Ruhr-University Bochum, D-44801 Bochum, Germany, and ⁵ Institute of Genetics, Division of Molecular Genetics, University of Bonn, 53117 Bonn, Germany

Compensatory mechanisms after genetic manipulations have been documented extensively for the nervous system. In many cases, these mechanisms involve genetic regulation at the transcription or expression level of existing isoforms. We report a novel mechanism by which single neurons compensate for changes in network connectivity by retuning their intrinsic electrical properties. We demonstrate this mechanism in the inferior olive, in which widespread electrical coupling is mediated by abundant gap junctions formed by connexin 36 (Cx36). It has been shown in various mammals that this electrical coupling supports the generation of subthreshold oscillations, but recent work revealed that rhythmic activity is sustained in knock-outs of Cx36. Thus, these results raise the question of whether the olivary oscillations in Cx36 knock-outs simply reflect the status of wild-type neurons without gap junctions or the outcome of compensatory mechanisms. Here, we demonstrate that the absence of Cx36 results in thicker dendrites with gap-junction-like structures with an abnormally wide interneuronal gap that prevents electrotonic coupling. The mutant olivary neurons show unusual voltage-dependent oscillations and an increased excitability that is attributable to a combined decrease in leak conductance and an increase in voltage-dependent calcium conductance. Using dynamic-clamp techniques, we demonstrated that these changes are sufficient to transform a wild-type neuron into a knock-out-like neuron. We conclude that the absence of Cx36 in the inferior olive is not compensated by the formation of other gap-junction channels but instead by changes in the cytological and electroresponsive properties of its neurons, such that the capability to produce rhythmic activity is maintained.

Key words: gap junction; electrotonic coupling; cerebellum; motor coordination; dynamic clamp; inferior olive; ultrastructure; connexins

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Received Jan. 31, 2003; revised Mar. 17, 2003; accepted Mar. 26, 2003.

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