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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 6. Behavioral phenotype of adult wt and IT mice. Performances of mice (latency to escape from the pool onto the platform) in the visible platform test of the Morris water maze task during 4 trials per day over 2 training days are shown. The fixed starting position of the mice is indicated by a black arrow while the varying positions of the platform are indicated by gray circles. Data represent the mean ± SEM; n = 13 for wt mice (black circles) and n = 11 for IT mice (gray circles). * p < 0.0.5 and *** p < 0.001 using a repeated-measures ANOVA and a post Fisher LSD test.
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Figure 6: Figure 6. Behavioral phenotype of adult wt and IT mice. Performances of mice (latency to escape from the pool onto the platform) in the visible platform test of the Morris water maze task during 4 trials per day over 2 training days are shown. The fixed starting position of the mice is indicated by a black arrow while the varying positions of the platform are indicated by gray circles. Data represent the mean ± SEM; n = 13 for wt mice (black circles) and n = 11 for IT mice (gray circles). * p < 0.0.5 and *** p < 0.001 using a repeated-measures ANOVA and a post Fisher LSD test.

Mentions: Finally, we investigated the role of Cav1.4 in visual function subjecting mice to established behavioral paradigms. Since these tests were all locomotion-based, we first screened for possible alterations in motor function. Wt and IT mice did not differ in novelty-induced locomotor activity (i.e., the distance traveled in the open field test and light/dark test or the total arm entries in the elevated plus maze test) as compared with wt (Table 2). Next, we assessed the visual performance of wt and IT mice subjecting them to the visual platform test of the Morris water maze37 (Fig. 6). The escape latency (latency to reach and climb the platform) gradually decreased with the increasing number of trials performed (repeated measures ANOVA: F(trial)7,154 = 10.689, p < 0.001) in both genotypes (F(trial × genotype)7,154 = 0.445, p = 0.872). However, in IT mice the latency was greatly increased as compared with wt (F(genotype)1,22 = 60.149, p < 0.001), pointing towards poor visual function of IT mice. In order to exclude a specific deficit in learning or memory-related processes as a cause for the impaired performance in the visible platform task of the Morris water maze, we tested the animals in an auditory cued fear-conditioning paradigm. Conditional responses, as indicated by freezing behavior, increased to the same extent in wt and IT mice upon 3 CS-footshock pairings (repeated measures ANOVA: F(pairing)4,88 = 62.502, p < 0.001; F(genotype)1,22 = 0.430, p = 0.519; F(pairing × genotype)4,88 = 0.6189, p = 0.650). On the next day in a novel context presentation of the CS alone did not elicit different freezing levels between the 2 genotypes suggesting normal learning capabilities of IT mice (percent freezing: wt 46.9 ± 5.5, IT 40.8 ± 5.2, t = 0.807, p = 0.428). Stimulated by human studies showing that the loss of vision has an impact on emotionality,38,39,40 we also investigated the anxiety-related behavior of IT mice. No differences in any anxiety-related parameter including the entries into or time spent in the center of the open field, the latency, entries and time in the open arms of the elevated plus maze or the latency, entries into and time spent in the light compartment of the light/dark test were observed as compared with wt (Table 2).


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 6. Behavioral phenotype of adult wt and IT mice. Performances of mice (latency to escape from the pool onto the platform) in the visible platform test of the Morris water maze task during 4 trials per day over 2 training days are shown. The fixed starting position of the mice is indicated by a black arrow while the varying positions of the platform are indicated by gray circles. Data represent the mean ± SEM; n = 13 for wt mice (black circles) and n = 11 for IT mice (gray circles). * p < 0.0.5 and *** p < 0.001 using a repeated-measures ANOVA and a post Fisher LSD test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Figure 6. Behavioral phenotype of adult wt and IT mice. Performances of mice (latency to escape from the pool onto the platform) in the visible platform test of the Morris water maze task during 4 trials per day over 2 training days are shown. The fixed starting position of the mice is indicated by a black arrow while the varying positions of the platform are indicated by gray circles. Data represent the mean ± SEM; n = 13 for wt mice (black circles) and n = 11 for IT mice (gray circles). * p < 0.0.5 and *** p < 0.001 using a repeated-measures ANOVA and a post Fisher LSD test.
Mentions: Finally, we investigated the role of Cav1.4 in visual function subjecting mice to established behavioral paradigms. Since these tests were all locomotion-based, we first screened for possible alterations in motor function. Wt and IT mice did not differ in novelty-induced locomotor activity (i.e., the distance traveled in the open field test and light/dark test or the total arm entries in the elevated plus maze test) as compared with wt (Table 2). Next, we assessed the visual performance of wt and IT mice subjecting them to the visual platform test of the Morris water maze37 (Fig. 6). The escape latency (latency to reach and climb the platform) gradually decreased with the increasing number of trials performed (repeated measures ANOVA: F(trial)7,154 = 10.689, p < 0.001) in both genotypes (F(trial × genotype)7,154 = 0.445, p = 0.872). However, in IT mice the latency was greatly increased as compared with wt (F(genotype)1,22 = 60.149, p < 0.001), pointing towards poor visual function of IT mice. In order to exclude a specific deficit in learning or memory-related processes as a cause for the impaired performance in the visible platform task of the Morris water maze, we tested the animals in an auditory cued fear-conditioning paradigm. Conditional responses, as indicated by freezing behavior, increased to the same extent in wt and IT mice upon 3 CS-footshock pairings (repeated measures ANOVA: F(pairing)4,88 = 62.502, p < 0.001; F(genotype)1,22 = 0.430, p = 0.519; F(pairing × genotype)4,88 = 0.6189, p = 0.650). On the next day in a novel context presentation of the CS alone did not elicit different freezing levels between the 2 genotypes suggesting normal learning capabilities of IT mice (percent freezing: wt 46.9 ± 5.5, IT 40.8 ± 5.2, t = 0.807, p = 0.428). Stimulated by human studies showing that the loss of vision has an impact on emotionality,38,39,40 we also investigated the anxiety-related behavior of IT mice. No differences in any anxiety-related parameter including the entries into or time spent in the center of the open field, the latency, entries and time in the open arms of the elevated plus maze or the latency, entries into and time spent in the light compartment of the light/dark test were observed as compared with wt (Table 2).

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