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Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2.

Knoflach D, Kerov V, Sartori SB, Obermair GJ, Schmuckermair C, Liu X, Sothilingam V, Garcia Garrido M, Baker SA, Glösmann M, Schicker K, Seeliger M, Lee A, Koschak A - Channels (Austin) (2013)

Bottom Line: Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated.Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter.The associated visual deficiency was substantiated in behavioral paradigms.

View Article: PubMed Central - PubMed

Affiliation: Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria.

ABSTRACT
Mutations in the CACNA1F gene encoding the Cav1.4 Ca (2+) channel are associated with X-linked congenital stationary night blindness type 2 (CSNB2). Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated. This work provides a thorough functional characterization of the novel IT mouse line that harbors the gain-of-function mutation I745T reported in a New Zealand CSNB2 family. (1) Electroretinographic recordings in IT mice permitted a direct comparison with human data. Our data supported the hypothesis that a hyperpolarizing shift in the voltage-dependence of channel activation-as seen in the IT gain-of-function mutant (2)-may reduce the dynamic range of photoreceptor activity. Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter. The organization of the outer plexiform layer was disrupted, and synaptic structures of photoreceptors had a variable, partly immature, appearance. The associated visual deficiency was substantiated in behavioral paradigms. The IT mouse line serves as a specific model for the functional phenotype of human CSNB2 patients with gain-of-function mutations and may help to further understand the dysfunction in CSNB.

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Figure 2. Morphological assessment of wt and IT mouse retinas. (A) In vivo OCT analysis of wt and IT mouse retinas, indicating (i) a reduction of the photoreceptor-containing outer nuclear layer (ONL), and (ii) a less expressed patterning of the inner/outer segment (IS/OS) border. (B) Retinal slices of adult wt (left) and IT (right) mice were stained with DAPI to show the nuclei. Light microscopic pictures from wt and IT were aligned at the GCL. Exemplar sections were taken from slices showing the same eccentricity. The reduction in the thickness of the ONL and INL in IT mice is evident (in [µm] for wt and IT respectively: ONL: 56 vs. 35; INL: 37 vs. 22). The arrow indicates the obvious misorganisation of the OPL. ONL, outer nuclear layer, INL, inner nuclear layer, GCL, ganglion cell layer. Scale bar 50 µm.
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Figure 2: Figure 2. Morphological assessment of wt and IT mouse retinas. (A) In vivo OCT analysis of wt and IT mouse retinas, indicating (i) a reduction of the photoreceptor-containing outer nuclear layer (ONL), and (ii) a less expressed patterning of the inner/outer segment (IS/OS) border. (B) Retinal slices of adult wt (left) and IT (right) mice were stained with DAPI to show the nuclei. Light microscopic pictures from wt and IT were aligned at the GCL. Exemplar sections were taken from slices showing the same eccentricity. The reduction in the thickness of the ONL and INL in IT mice is evident (in [µm] for wt and IT respectively: ONL: 56 vs. 35; INL: 37 vs. 22). The arrow indicates the obvious misorganisation of the OPL. ONL, outer nuclear layer, INL, inner nuclear layer, GCL, ganglion cell layer. Scale bar 50 µm.

Mentions: Optical coherence tomography (OCT) of retinal substructures/layers in vivo indicated a distinct reduction in the outer plexiform layer (OPL) thickness in the mutant mice (Fig. 2A). This finding is in line with our histomorphological analysis (Fig. 2B). Specifically, a DAPI staining was performed on retinal sections of adult (2 mo-old) mice to compare the thickness of the retina as well as that of the major retinal layers at three different eccentricities in wt and IT. At comparable eccentricities, the rows of nuclei in the outer nuclear layer (ONL) were counted. Gross retinal structure and layering were normal in IT mice. All retinal layers were present. However, the number of rows of nuclei in the ONL was lower in IT than in wt mice resulting in a reduction in the thickness of the ONL and the total retinal thickness (Fig. 2B). OCT further revealed a less expressed patterning of the inner/outer segment (IS/OS) border that is indicative of irregular outer retinal layering (Fig. 2A).


Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2.

Knoflach D, Kerov V, Sartori SB, Obermair GJ, Schmuckermair C, Liu X, Sothilingam V, Garcia Garrido M, Baker SA, Glösmann M, Schicker K, Seeliger M, Lee A, Koschak A - Channels (Austin) (2013)

Figure 2. Morphological assessment of wt and IT mouse retinas. (A) In vivo OCT analysis of wt and IT mouse retinas, indicating (i) a reduction of the photoreceptor-containing outer nuclear layer (ONL), and (ii) a less expressed patterning of the inner/outer segment (IS/OS) border. (B) Retinal slices of adult wt (left) and IT (right) mice were stained with DAPI to show the nuclei. Light microscopic pictures from wt and IT were aligned at the GCL. Exemplar sections were taken from slices showing the same eccentricity. The reduction in the thickness of the ONL and INL in IT mice is evident (in [µm] for wt and IT respectively: ONL: 56 vs. 35; INL: 37 vs. 22). The arrow indicates the obvious misorganisation of the OPL. ONL, outer nuclear layer, INL, inner nuclear layer, GCL, ganglion cell layer. Scale bar 50 µm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042485&req=5

Figure 2: Figure 2. Morphological assessment of wt and IT mouse retinas. (A) In vivo OCT analysis of wt and IT mouse retinas, indicating (i) a reduction of the photoreceptor-containing outer nuclear layer (ONL), and (ii) a less expressed patterning of the inner/outer segment (IS/OS) border. (B) Retinal slices of adult wt (left) and IT (right) mice were stained with DAPI to show the nuclei. Light microscopic pictures from wt and IT were aligned at the GCL. Exemplar sections were taken from slices showing the same eccentricity. The reduction in the thickness of the ONL and INL in IT mice is evident (in [µm] for wt and IT respectively: ONL: 56 vs. 35; INL: 37 vs. 22). The arrow indicates the obvious misorganisation of the OPL. ONL, outer nuclear layer, INL, inner nuclear layer, GCL, ganglion cell layer. Scale bar 50 µm.
Mentions: Optical coherence tomography (OCT) of retinal substructures/layers in vivo indicated a distinct reduction in the outer plexiform layer (OPL) thickness in the mutant mice (Fig. 2A). This finding is in line with our histomorphological analysis (Fig. 2B). Specifically, a DAPI staining was performed on retinal sections of adult (2 mo-old) mice to compare the thickness of the retina as well as that of the major retinal layers at three different eccentricities in wt and IT. At comparable eccentricities, the rows of nuclei in the outer nuclear layer (ONL) were counted. Gross retinal structure and layering were normal in IT mice. All retinal layers were present. However, the number of rows of nuclei in the ONL was lower in IT than in wt mice resulting in a reduction in the thickness of the ONL and the total retinal thickness (Fig. 2B). OCT further revealed a less expressed patterning of the inner/outer segment (IS/OS) border that is indicative of irregular outer retinal layering (Fig. 2A).

Bottom Line: Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated.Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter.The associated visual deficiency was substantiated in behavioral paradigms.

View Article: PubMed Central - PubMed

Affiliation: Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria.

ABSTRACT
Mutations in the CACNA1F gene encoding the Cav1.4 Ca (2+) channel are associated with X-linked congenital stationary night blindness type 2 (CSNB2). Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated. This work provides a thorough functional characterization of the novel IT mouse line that harbors the gain-of-function mutation I745T reported in a New Zealand CSNB2 family. (1) Electroretinographic recordings in IT mice permitted a direct comparison with human data. Our data supported the hypothesis that a hyperpolarizing shift in the voltage-dependence of channel activation-as seen in the IT gain-of-function mutant (2)-may reduce the dynamic range of photoreceptor activity. Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter. The organization of the outer plexiform layer was disrupted, and synaptic structures of photoreceptors had a variable, partly immature, appearance. The associated visual deficiency was substantiated in behavioral paradigms. The IT mouse line serves as a specific model for the functional phenotype of human CSNB2 patients with gain-of-function mutations and may help to further understand the dysfunction in CSNB.

Show MeSH
Related in: MedlinePlus