title: Cav1.3 calcium channels are required for normal development of the auditory brainstem.
abstract: Within the Ca(v)1 family of voltage-gated calcium channels, Ca(v)1.2 and Ca(v)1.3 channels are the predominant subtypes in the brain. Whereas specific functions for each subtype were described in the adult brain, their role in brain development is poorly understood. Here we assess the role of Ca(v)1.3 subunits in the activity-dependent development of the auditory brainstem. We used Ca(v)1.3-deficient (Ca(v)1.3(-/-)) mice because these mice lack cochlea-driven activity that deprives the auditory centers from peripheral input. We found a drastically reduced volume in all auditory brainstem centers (range 25-59%, total 35%), which was manifest before hearing onset. A reduction was not obvious outside the auditory system. The lateral superior olive (LSO) was strikingly malformed in Ca(v)1.3(-/-) mice and had fewer neurons (1/3 less). The remaining LSO neurons displayed normal dendritic trees and received functional glutamatergic input, yet they fired action potentials predominantly with a multiple pattern upon depolarization, in contrast to the single firing pattern prevalent in controls. The latter finding appears to be due to a reduction of dendrototoxin-sensitive potassium conductances, presumably mediated through the K(v)1.2 subtype. Fura2 imaging provided evidence for functional Ca(v)1.3 channels in the LSO of wild-type mice. Our results imply that Ca(v)1.3 channels are indispensable for the development of the central auditory system. We propose that the unique LSO phenotype in Ca(v)1.3(-/-) mice, which hitherto was not described in other hereditary deafness models, is caused by the synergistic contribution of two factors: on-site loss of Ca(v)1.3 channels in the neurons plus lack of peripheral input.
authors.affiliation: Department of Biology, University of Kaiserslautern, D-67653 Kaiserslautern, Germany.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Hirtz
authors.forename: Michael
authors.initials: M
authors.lastname: Boesen
authors.forename: Nadine
authors.initials: N
authors.lastname: Braun
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Deitmer
authors.forename: Florian
authors.initials: F
authors.lastname: Kramer
authors.forename: Christian
authors.initials: C
authors.lastname: Lohr
authors.forename: Britta
authors.initials: B
authors.lastname: Müller
authors.forename: Hans Gerd
authors.initials: HG
authors.lastname: Nothwang
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
authors.forename: Stefan
authors.initials: S
authors.lastname: Löhrke
authors.forename: Eckhard
authors.initials: E
authors.lastname: Friauf
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001284:Atrophy / Q000473:pathology; D001933:Brain Stem / Q000166:cytology / Q000254:growth & development* / Q000473:pathology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D002452:Cell Count / Q000706:statistics & numerical data; D004546:Elapid Venoms / Q000494:pharmacology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
chemical_list: C485995:Cacna1d protein, mouse; D020746:Calcium Channels, L-Type; D004546:Elapid Venoms; D016194:Receptors, N-Methyl-D-Aspartate; C020273:dendrotoxin