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N.C. Orton, F.C. Mansergh, J.P. Vessey, M. Lalonde, F. Tremblay, S. Barnes, D.E. Rancourt, W.K. Stell, N.T. Bech–Hansen; Mutation of the Calcium Channel Gene Cacna1f Disrupts Calcium Signaling and Synaptic Transmission in Mouse Retina . Invest. Ophthalmol. Vis. Sci. 2004;45(13):2507.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Mutations in CACNA1F, which encodes the Cav1.4 (α1F) subunit of a voltage–gated L–type calcium channel, cause X–linked incomplete congenital stationary night blindness (iCSNB). iCSNB is characterized by a ‘negative ERG’. We have constructed a murine model of iCSNB by targeted–disruption of the Cacna1f gene. Electrophysiological and morphological studies of the retina of this mouse provide the opportunity for evaluating the retinal physiology, neuronal morphology, and genetic complexity associated with iCSNB. Methods: ERG and calcium imaging were used to assess the retinal physiology of the Cacna1f (–/y) mice. The morphology of representative retinal neurons was evaluated systematically with immunocytochemistry using cell type specific antibodies and fluorescence microscopy. Results: ERGs in the KO mice revealed a scotopic bright–flash response with electronegative configuration. The a–wave amplitude, implicit time or sensitivity did not differ from the ones obtained from controls. No oscillatory potentials could be detected in any responses. Cone responses were extinguished and the ON–OFF responses showed only evidence for photoreceptor contribution. Furthermore, calcium imaging showed that photoreceptors of mutant mice responded to K+ depolarization by increasing their calcium levels one tenth as much as in normal littermates, while cells of the inner nuclear layer and ganglion cells responded equally well to K+ depolarization in mutants and littermates. We found pronounced morphological changes in second order neurons. Rod bipolar (PKCα) and horizontal cell (calbindin) processes exhibited abnormal dendritic sprouting, extending deep into the ONL. Key components of the synaptic ribbon (kinesin, bassoon) were present in the ONL in close apposition to these aberrant neurons suggesting the presence of ectopic synapses. Conclusions: The absence of post–receptoral ERG responses and diminished photoreceptor calcium signals in our Cacna1f–targeted knockout mouse are consistent with a loss of calcium channel function in photoreceptors. The morphology of second order neurons is abnormal and ectopic photoreceptor synapses are present in the ONL. Together, these studies of a mutant Cacna1f mouse show the selective functional defect, and expand our understanding of iCSNB as a retinal channelopathy.
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