title: 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.
abstract: 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.
authors.affiliation: Department of Neuroscience, Medical Faculty, Erasmus MC, 3000DR Rotterdam, The Netherlands. c.dezeeuw@erasmusmc.nl
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.forename: Edilzh
authors.initials: E
authors.lastname: Chorev
authors.forename: Anna
authors.initials: A
authors.lastname: Devor
authors.forename: Yait
authors.initials: Y
authors.lastname: Manor
authors.forename: Ruben S
authors.initials: RS
authors.lastname: Van Der Giessen
authors.forename: Marcel T
authors.initials: MT
authors.lastname: De Jeu
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.forename: Jan
authors.initials: J
authors.lastname: Bijman
authors.forename: Tom J H
authors.initials: TJ
authors.lastname: Ruigrok
authors.forename: Pim
authors.initials: P
authors.lastname: French
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
authors.forename: Werner M
authors.initials: WM
authors.lastname: Kistler
authors.forename: Carola
authors.initials: C
authors.lastname: Meier
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petrasch-Parwez
authors.forename: Rolf
authors.initials: R
authors.lastname: Dermietzel
authors.forename: Goran
authors.initials: G
authors.lastname: Sohl
authors.forename: Martin
authors.initials: M
authors.lastname: Gueldenagel
authors.forename: Klaus
authors.initials: K
authors.lastname: Willecke
authors.forename: Yosi
authors.initials: Y
authors.lastname: Yarom
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics / Q000502:physiology; D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D017630:Connexins / Q000172:deficiency* / Q000235:genetics; D003712:Dendrites / Q000473:pathology / Q000648:ultrastructure; D004594:Electrophysiology; D017629:Gap Junctions / Q000235:genetics / Q000473:pathology / Q000648:ultrastructure; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000503:physiopathology*; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000473:pathology* / Q000502:physiology*; D019581:Neuropil / Q000473:pathology; D009847:Olivary Nucleus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D010507:Periodicity; D012333:RNA, Messenger / Q000096:biosynthesis; D000097004:Gap Junction delta-2 Protein
chemical_list: D002118:Calcium; D017630:Connexins; D012333:RNA, Messenger; D000097004:Gap Junction delta-2 Protein