Synaptic effects of mutations in neuronal Ca
V2.1 calcium channels Simon Kaja
Ca2+ Ca2+
SynaptiC effeCtS of MutationS in neuRonaL Ca
V2.1 CaLCiuM ChanneLS
SiMon Kaja
Simon Kaja
Synaptic effects of mutations in neuronal CaV2.1 calcium channels.
ph.D. thesis, university of Leiden, 6th february 2007
iSBn-10: 0-9781905-0-5 iSBn-13: 978-0-9781905-0-7
© 2006, 2007 Simon Kaja
Copyright of individual chapters rests with the author(s), with the following exceptions:
Chapter 2: Cell press Chapter 3: elsevier Ltd.
Chapter 6: the american physiological Society Chapter 7: elsevier Ltd.
Chapter 8: Wiley-Liss, inc.
No part of this thesis may be reproduced in any form, by print, photocopy, digital file, or any other means without prior written permission from the author.
printed by: ponsen en Looijen, Wageningen, the netherlands Cover Design: Simon Kaja
Synaptic effects of mutations in neuronal Ca
V2.1 calcium channels
Proefschrift
ter verkrijging van
de graad van Doctor aan de universiteit Leiden, op gezag van de Rector Magnificus Dr. D.D. Breimer,
hoogleraar in de faculteit der Wiskunde en natuurwetenschappen en die der Geneeskunde,
volgens besluit van het College voor promoties te verdedigen op dinsdag 6 februari 2007
klokke 13:45 uur
door
Simon Kaja
geboren te Düsseldorf in 1979
Promotiecommissie Promotores
prof.dr. M.D. ferrari prof.dr. R.R. frants Co-Promotor Dr. j.j. plomp referent
prof. C.R. Slater, university of newcastle upon tyne, uK overigeleden
prof.dr. j.G. van Dijk prof.dr. h.j. tanke
Most experiments described in thesis were performed at the: - Leiden university Medical Centre
Department of Molecular Cell Biology neurophysiology Laboratory Dr. j.j. plomp einthovenweg 20, p.o. Box 9600
nL- 2300 RC Leiden the netherlands
the studies described in thesis were supported by grants from the prinses Beatrix fonds (#MaR01-0105) and hersenstichting nederland (#9f01(2).24).
financial support for the printing of this thesis was generously provided by: - GlaxoSmithKline b.v., janssen-Cilag b.v., Koninklijke nederlandse akademie van Wetenschappen Van Leersumfonds, Menarini farma b.v., Merck Sharp & Dohme b.v., MS Vision, and the nederlandse hoofdpijn Vereniging.
“If the brain were so simple we could understand it, we would be so simple we couldn’t.”
Lyall Watson
for my parents
Synaptic EffEctSof MutationS in nEuronal caV2.1 calciuM channElS
8
tablEof contEntS
9
Contents
Chapters page
1 General introduction 11
2 A Cacna1a knockin migraine mouse model with increased susceptibility to 31 cortical spreading depression.
Neuron (2004) 41:701-710
3 Gene dosage-dependent transmitter release changes at neuromuscular 47 synapses of Cacna1a R192Q knockin mice are non-progressive and do not
lead to morphological changes or muscle weakness.
Neuroscience (2005) 135:81-95
4 Severe and progressive neurotransmitter release aberrations in a novel 67 familial hemiplegic migraine Cacna1a S218L knock-in mouse.
To be submitted
5 Compensatory contribution of CaV2.3 channels to acetylcholine release 85 at the neuromuscular junction of Tottering mice.
Journal of Neurophysiology (2006) 95:2698-2704
6 Severely impaired neuromuscular synaptic transmission causes muscle 97 weakness in the Cacna1a mutant mouse rolling Nagoya.
Submitted
7 Characterization of acetylcholine release and compensatory contribution 115 of non-CaV2.1 channels at motor nerve terminals of Leaner CaV2.1 mutant
mice.
Neuroscience, in press
8 Conditional inactivation of the Cacna1a gene in transgenic mice. 129 Genesis, in press
9 Reduced ACh release at neuromuscular synapses of heterozygous 137 Leaner mice.
To be submitted
10 Redundancy of accessory subunits of CaV2.1 channels in transmitter 149 release at the mouse neuromuscular junction.
Submitted
11 No direct effect of topiramate on wild-type and mutant CaV2.1 channels 163 mediating acetylcholine release mouse neuromuscular synapses.
To be submitted
12 General discussion 171
appendiCes page
List of references 185
Summary / Samenvatting / Zusammenfassung / Sommaire 201
List of Abbreviations 221
Bibliography 223
Curriculum Vitae 225
Synaptic EffEctSof MutationS in nEuronal caV2.1 calciuM channElS
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