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Human Molecular Genetics Advance Access originally published online on September 9, 2005
Human Molecular Genetics 2005 14(20):3035-3046; doi:10.1093/hmg/ddi336
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mutation of the calcium channel gene Cacna1f disrupts calcium signaling, synaptic transmission and cellular organization in mouse retina

Fiona Mansergh1,2,{dagger},{ddagger}, Noelle C. Orton3,{dagger}, John P. Vessey10,11,12, Melanie R. Lalonde10,11,12, William K. Stell4,5,6,8, Francois Tremblay10,11,12, Steven Barnes10,11,12, Derrick E. Rancourt1,2 and N. Torben Bech-Hansen3,5,6,7,9,*

1Department of Oncology, 2Department of Biochemistry and Molecular Biology, 3Department of Medical Genetics, 4Department of Cell Biology and Anatomy, 5Department of Surgery, 6Lion's Sight Centre, 7Population Genomics, 8Neurosciences Research Groups and 9Institute of Maternal and Child Health, Faculty of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1, 10Department of Physiology and Biophysics and 11Department of Ophthalmology and 12Retina Research Laboratory, Dalhousie University, Halifax, NS, Canada

* To whom correspondence should be addressed at: Department of Medical Genetics, Faculty of Medicine, University of Calgary, 3330 Hospital Drive, N.W., Calgary, Alberta, Canada T2N 4N1. Tel: +1 4032208387; Fax: +1 4032108119; Email: ntbech{at}ucalgary.ca

Received August 8, 2005; Accepted September 6, 2005

Retinal neural transmission represents a key function of the eye. Identifying the molecular components of this vital process is helped by studies of selected human genetic eye disorders. For example, mutations in the calcium channel subunit gene CACNA1F cause incomplete X-linked congenital stationary night blindness (CSNB2 or iCSNB), a human retinal disorder with abnormal electrophysiological response and visual impairments consistent with a retinal neurotransmission defect. To understand the subcellular basis of this retinal disorder, we generated a mouse with a loss-of-function mutation by inserting a self-excising Cre-lox-neo cassette into exon 7 of the murine orthologue, Cacna1f. Electroretinography of the mutant mouse revealed a scotopic a-wave of marginally reduced amplitude compared with the wild-type mouse and absence of the post-receptoral b-wave and oscillatory potentials. Cone ERG responses together with visual evoked potentials and multi-unit activity in the superior colliculus were also absent. Calcium imaging in Fluo-4 loaded retinal slices depolarized with KCl showed 90% less peak signal in the photoreceptor synapses of the Cacna1f mutant than in wild-type mice. The absence of post-receptoral ERG responses and the diminished photoreceptor calcium signals are consistent with a loss of Ca2+ channel function in photoreceptors. Immunocytochemistry showed no detectable Cav1.4 protein in the outer plexiform layer of Cacna1f-mutant mice, profound loss of photoreceptor synapses, and abnormal dendritic sprouting of second-order neurons in the photoreceptor layer. Together, these findings in the Cacna1f-mutant mouse reveal that the Cav1.4 calcium channel is vital for the functional assembly and/or maintenance and synaptic functions of photoreceptor ribbon synapses. Moreover, the outcome of this study provides critical clues to the pathophysiology of the human retinal channelopathy of X-linked incomplete CSNB.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.

{ddagger} Present address: Department of Biosciences, Cardiff University, Biomedical Sciences Building, Museum Avenue, Cardiff, UK.


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