Synaptic effects of mutations in neuronal Cav2.1 calcium channels.

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Synaptic effects of mutations in neuronal Cav2.1 calcium channels.

Type: Doctoral Thesis
Title: Synaptic effects of mutations in neuronal Cav2.1 calcium channels.
Author: Kaja, Simon
Publisher: Leiden Department of Neurology and Department of Molecular Cell Biology, Section Neurophysiology, Faculty of Medicine / Leiden University Medical Center (LUMC), Leiden University
Issue Date: 2007-02-06
Keywords: Electrophysiology
Abstract: Mutations in the CACNA1A gene, encoding neuronal Cav2.1 calcium channels, cause a wide spectrum of human neurological diseases, including familial hemiplegic migraine type 1 (FHM1). The role of Cav2.1 channels is to mediate neurotransmitter release. Using electrophysiological techniques, this thesis investigates the effects of several CACNA1A mutations on neurotransmitter release at the mouse neuromuscular junction (NMJ). It is concluded that the FHM1 mutations R192Q and S218L increase neurotransmitter release and do not result in compensatory contributions of other types of calcium channels. Furthermore, it is shown that spontaneous neurotransmitter at the mouse NMJ is partly Cav2.1 channel-dependent, whereas evoked release relies entirely on Cav2.1 channels. Studies on the Cav2.1 mouse mutant Rolling Nagoya show that spontaneous and evoked neurotransmitter release are controlled independently. Studies on mouse mutants that lack auxiliary Cav2.1 channel subunits revealed that these subunits are redundant and/or absent at the mouse NMJ. The studies presented in this thesis provide novel insights into the synaptic dysfunction caused by Cav2.1 channel mutations. Synaptic effects on central synapses are likely to share many features with those observed at the mouse NMJ and thought to underlie (some of) the neurological symptoms of human and mouse disorders associated with Cav2.1 channel dysfunction.
Description: Promotores: M.D. Ferrari, R.R. Frants, Co-promotor: J.J. Plomp
With summary in Dutch, German, French
Faculty: Faculteit der Wiskunde en Natuurwetenschappen
Citation: Kaja, S., 2007, Doctoral thesis, Leiden University
ISBN: 0978190505
Sponsor: Prinses Beatrix Fonds (#MAR01-0105) Hersenstichting Nederland (#9F01(2).24)

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text/html Links to published articles 16.25Kb View/Open
application/pdf Title page_Table of contents 219.3Kb View/Open
application/pdf Chapter 1 - Introduction 563.9Kb View/Open
application/pdf Chapter 2 - Generation of FHM1 R192Q Knockin Mice 1.125Mb View/Open
application/pdf Chapter 3 - Ele ... tion of R192Q Knockin Mice 1.347Mb View/Open
application/pdf Chapter 4 929.0Kb View/Open
application/pdf Chapter 5 - Com ... Channels at Tottering NMJs 588.2Kb View/Open
application/pdf Chapter 6 676.6Kb View/Open
application/pdf Chapter 7 - Cha ... nd Null Cav2.1 Mutant Mice 1.236Mb View/Open
application/pdf Chapter 8 - Generation of Conditional Cacna1a Mice 488.4Kb View/Open
application/pdf Chapter 9 611.0Kb View/Open
application/pdf Chapter 10 686.8Kb View/Open
application/pdf Chapter 11 488.2Kb View/Open
application/pdf Chapter 12 - General Discussion and Conclusions 371.0Kb View/Open
application/pdf List of Referen ... liography_Curriculum Vitae 490.4Kb View/Open
application/pdf Propositions 154.3Kb View/Open

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