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Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2.

Liu X, Kerov V, Haeseleer F, Majumder A, Artemyev N, Baker SA, Lee A - Channels (Austin) (2013)

Bottom Line: Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina.However, after postnatal day 13, many PR ribbons retain the immature morphology.Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics; University of Iowa; Iowa City, IA USA; Departments of Otolaryngology-Head and Neck Surgery, and Neurology; University of Iowa; Iowa City, IA USA.

ABSTRACT
Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav 1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav 1.4 channels. Whether defects in PR synapse development due to altered Cav 1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav 1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav 1.4 activation is either enhanced (Cav 1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav 1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.

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Figure 3. Cav1.4 is required for synapse formation. (A) Immunofluorescence for RIBEYE (green) and Cav1.4 (red) in retina from WT mice (P5-P15). (B) Immunofluorescence for RIBEYE (green) and GluR2 in retina from WT (left) and Cav1.4 KO (right) mice (P5-P15). Mature (arrows) and immature (arrowheads) ribbon morphologies are indicated. Scale bars: 2 μm. Results shown are representative of at least 3 independent experiments.
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Figure 3: Figure 3. Cav1.4 is required for synapse formation. (A) Immunofluorescence for RIBEYE (green) and Cav1.4 (red) in retina from WT mice (P5-P15). (B) Immunofluorescence for RIBEYE (green) and GluR2 in retina from WT (left) and Cav1.4 KO (right) mice (P5-P15). Mature (arrows) and immature (arrowheads) ribbon morphologies are indicated. Scale bars: 2 μm. Results shown are representative of at least 3 independent experiments.

Mentions: Using these Cav1.4-selective antibodies, we profiled the distribution of Cav1.4 at developing PR synapses from P5-P15 in the mouse retina. From P5-P8, labeling for Cav1.4 and RIBEYE was largely colocalized in small puncta resembling ribbon precursor spheres11,12 in the OPL (Fig. 3A). Between P11-P15, Cav1.4-labeled ribbons become more elongated, and depending on the plane of section, take on the horseshoe-shaped morphology of mature rod PR synapses (Fig. 3A).11 The temporal and spatial coincidence of Cav1.4 and RIBEYE labeling in the OPL is consistent with a role for Cav1.4 channels in directing PR synapse assembly.


Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2.

Liu X, Kerov V, Haeseleer F, Majumder A, Artemyev N, Baker SA, Lee A - Channels (Austin) (2013)

Figure 3. Cav1.4 is required for synapse formation. (A) Immunofluorescence for RIBEYE (green) and Cav1.4 (red) in retina from WT mice (P5-P15). (B) Immunofluorescence for RIBEYE (green) and GluR2 in retina from WT (left) and Cav1.4 KO (right) mice (P5-P15). Mature (arrows) and immature (arrowheads) ribbon morphologies are indicated. Scale bars: 2 μm. Results shown are representative of at least 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042486&req=5

Figure 3: Figure 3. Cav1.4 is required for synapse formation. (A) Immunofluorescence for RIBEYE (green) and Cav1.4 (red) in retina from WT mice (P5-P15). (B) Immunofluorescence for RIBEYE (green) and GluR2 in retina from WT (left) and Cav1.4 KO (right) mice (P5-P15). Mature (arrows) and immature (arrowheads) ribbon morphologies are indicated. Scale bars: 2 μm. Results shown are representative of at least 3 independent experiments.
Mentions: Using these Cav1.4-selective antibodies, we profiled the distribution of Cav1.4 at developing PR synapses from P5-P15 in the mouse retina. From P5-P8, labeling for Cav1.4 and RIBEYE was largely colocalized in small puncta resembling ribbon precursor spheres11,12 in the OPL (Fig. 3A). Between P11-P15, Cav1.4-labeled ribbons become more elongated, and depending on the plane of section, take on the horseshoe-shaped morphology of mature rod PR synapses (Fig. 3A).11 The temporal and spatial coincidence of Cav1.4 and RIBEYE labeling in the OPL is consistent with a role for Cav1.4 channels in directing PR synapse assembly.

Bottom Line: Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina.However, after postnatal day 13, many PR ribbons retain the immature morphology.Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Physiology and Biophysics; University of Iowa; Iowa City, IA USA; Departments of Otolaryngology-Head and Neck Surgery, and Neurology; University of Iowa; Iowa City, IA USA.

ABSTRACT
Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav 1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav 1.4 channels. Whether defects in PR synapse development due to altered Cav 1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav 1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav 1.4 activation is either enhanced (Cav 1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav 1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.

Show MeSH
Related in: MedlinePlus