Journal article
α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses
The Journal of neuroscience, Vol.38(27), pp.6145-6160
07/04/2018
DOI: 10.1523/JNEUROSCI.3818-16.2018
PMCID: PMC6031576
PMID: 29875267
Abstract
α
2
δ-4 is an auxiliary subunit of voltage-gated Ca
v
1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the
CACNA2D4
gene encoding α
2
δ-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of α
2
δ-4, we used genome editing to generate an α
2
δ-4 knock-out (α
2
δ-4 KO) mouse. In male and female α
2
δ-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in α
2
δ-4 KO retina. In reconstructions of α
2
δ-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in α
2
δ-4 KO mice correlates with a progressive loss of Ca
v
1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in α
2
δ-4 KO mice and better under photopic than scotopic conditions. We conclude that α
2
δ-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with
CACNA2D4
mutations.
SIGNIFICANCE STATEMENT
In the retina, visual information is first communicated by the synapse formed between photoreceptors and second-order neurons. The mechanisms that regulate the structural integrity of this synapse are poorly understood. Here we demonstrate a role for α
2
δ-4, a subunit of voltage-gated Ca
2+
channels, in organizing the structure and function of photoreceptor synapses. We find that presynaptic Ca
2+
channels are progressively lost and that rod and cone synapses are disrupted in mice that lack α
2
δ-4. Our results suggest that alterations in presynaptic Ca
2+
signaling and photoreceptor synapse structure may contribute to vision impairment in humans with mutations in the
CACNA2D4
gene encoding α
2
δ-4.
Details
- Title: Subtitle
- α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses
- Creators
- Vasily Kerov - Department of Molecular Physiology and BiophysicsJoseph G Laird - Department of BiochemistryMei-ling Joiner - Department of Molecular Physiology and BiophysicsSharmon Knecht - Department of Biological Structure, University of Washington, Seattle, Washington 98195, andDaniel Soh - Department of Molecular Physiology and BiophysicsJussara Hagen - Department of Molecular Physiology and BiophysicsSarah H Gardner - Department of BiochemistryWade Gutierrez - Medical Scientist Training ProgramTakeshi Yoshimatsu - Department of Biological Structure, University of Washington, Seattle, Washington 98195, andSajag Bhattarai - Department of Ophthalmology and Institute for Vision ResearchTeresa Puthussery - Casey Eye Institute, Oregon Health & Science University, Portland, Oregon 97239Nikolai O Artemyev - Department of Molecular Physiology and BiophysicsArlene V Drack - Department of Ophthalmology and Institute for Vision ResearchRachel O Wong - Department of Biological Structure, University of Washington, Seattle, Washington 98195, andSheila A Baker - Department of BiochemistryAmy Lee - Department of Molecular Physiology and Biophysics
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.38(27), pp.6145-6160
- Publisher
- Society for Neuroscience
- DOI
- 10.1523/JNEUROSCI.3818-16.2018
- PMID
- 29875267
- PMCID
- PMC6031576
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Language
- English
- Date published
- 07/04/2018
- Academic Unit
- Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biology; Biochemistry and Molecular Biology; University College Courses; Ophthalmology and Visual Sciences
- Record Identifier
- 9984025260602771
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