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A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

Morgan JP, Magee H, Wong A, Nelson T, Koch B, Cooper JD, Weimer JM - PLoS ONE (2013)

Bottom Line: Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes.As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation.Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Biomedical Sciences. Sanford School of Medicine at the University of South Dakota, Vermillion, South Dakota, United States of America ; Children's Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America.

ABSTRACT
Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

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Decreased motor coordination deficits in Cln6nclf mice.(A) Rotarod testing was performed on postnatal day 14, 28, 90, and 270 old WT and Cln6nclf mice. Data are plotted as average latency to fall from the rotating rod during a 240 second trial period (3 trials per mouse per time point). Cln6nclf mice had a significant reduction in their ability to remain on the rod as it accelerated, starting at P90 and continuing at P270. (B–C) At six months of age, no difference was noted in additional motor performance measures including the time required to descend in a pole climb test (B) or the mean distance traveled (in meters) over a 15-min test period in an open field activity test (C). [Mean +/− SEM, n = 6–9 mice per group (**p≤0.01, ***p≤0.0001)].
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pone-0078694-g002: Decreased motor coordination deficits in Cln6nclf mice.(A) Rotarod testing was performed on postnatal day 14, 28, 90, and 270 old WT and Cln6nclf mice. Data are plotted as average latency to fall from the rotating rod during a 240 second trial period (3 trials per mouse per time point). Cln6nclf mice had a significant reduction in their ability to remain on the rod as it accelerated, starting at P90 and continuing at P270. (B–C) At six months of age, no difference was noted in additional motor performance measures including the time required to descend in a pole climb test (B) or the mean distance traveled (in meters) over a 15-min test period in an open field activity test (C). [Mean +/− SEM, n = 6–9 mice per group (**p≤0.01, ***p≤0.0001)].

Mentions: NCL patients often display severe motor dysfunction with symptoms presenting in vLINCL patients at approximately 18 months of age and including progressive motor delay, dysarthria, and ataxia ([10], [55], Reviewed in [56]). Here, we examine motor performance in Cln6nclf mice using several motor performance assays. First, rotarod testing was used to measure the ability of the mice to maintain their balance on a spinning rod. At P14 and P28 there is no difference in the latency to fall from the rod (Fig. 2 A). However, by 3 months there is a dramatic reduction in the ability of the mice to remain on the rod, indicating motor coordination and balance deficits. These deficits worsen over time, demonstrating early onset and progressive motor decline in this animal model of vLINCL (Fig. 2 A). General motor activity tests were performed using a standard pole climb and open field activity tests (Fig. 2 C–D), although no differences were noted at 6 months of age (pole climb, p = 0.22; open field, p = 0.1), suggesting these deficits are specific to balance and coordination.


A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease.

Morgan JP, Magee H, Wong A, Nelson T, Koch B, Cooper JD, Weimer JM - PLoS ONE (2013)

Decreased motor coordination deficits in Cln6nclf mice.(A) Rotarod testing was performed on postnatal day 14, 28, 90, and 270 old WT and Cln6nclf mice. Data are plotted as average latency to fall from the rotating rod during a 240 second trial period (3 trials per mouse per time point). Cln6nclf mice had a significant reduction in their ability to remain on the rod as it accelerated, starting at P90 and continuing at P270. (B–C) At six months of age, no difference was noted in additional motor performance measures including the time required to descend in a pole climb test (B) or the mean distance traveled (in meters) over a 15-min test period in an open field activity test (C). [Mean +/− SEM, n = 6–9 mice per group (**p≤0.01, ***p≤0.0001)].
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815212&req=5

pone-0078694-g002: Decreased motor coordination deficits in Cln6nclf mice.(A) Rotarod testing was performed on postnatal day 14, 28, 90, and 270 old WT and Cln6nclf mice. Data are plotted as average latency to fall from the rotating rod during a 240 second trial period (3 trials per mouse per time point). Cln6nclf mice had a significant reduction in their ability to remain on the rod as it accelerated, starting at P90 and continuing at P270. (B–C) At six months of age, no difference was noted in additional motor performance measures including the time required to descend in a pole climb test (B) or the mean distance traveled (in meters) over a 15-min test period in an open field activity test (C). [Mean +/− SEM, n = 6–9 mice per group (**p≤0.01, ***p≤0.0001)].
Mentions: NCL patients often display severe motor dysfunction with symptoms presenting in vLINCL patients at approximately 18 months of age and including progressive motor delay, dysarthria, and ataxia ([10], [55], Reviewed in [56]). Here, we examine motor performance in Cln6nclf mice using several motor performance assays. First, rotarod testing was used to measure the ability of the mice to maintain their balance on a spinning rod. At P14 and P28 there is no difference in the latency to fall from the rod (Fig. 2 A). However, by 3 months there is a dramatic reduction in the ability of the mice to remain on the rod, indicating motor coordination and balance deficits. These deficits worsen over time, demonstrating early onset and progressive motor decline in this animal model of vLINCL (Fig. 2 A). General motor activity tests were performed using a standard pole climb and open field activity tests (Fig. 2 C–D), although no differences were noted at 6 months of age (pole climb, p = 0.22; open field, p = 0.1), suggesting these deficits are specific to balance and coordination.

Bottom Line: Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes.As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation.Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6.

View Article: PubMed Central - PubMed

Affiliation: Division of Basic Biomedical Sciences. Sanford School of Medicine at the University of South Dakota, Vermillion, South Dakota, United States of America ; Children's Health Research Center, Sanford Research/USD, Sioux Falls, South Dakota, United States of America.

ABSTRACT
Neuronal ceroid lipofuscinoses (NCLs; also known collectively as Batten Disease) are a family of autosomal recessive lysosomal storage disorders. Mutations in as many as 13 genes give rise to ∼10 variants of NCL, all with overlapping clinical symptomatology including visual impairment, motor and cognitive dysfunction, seizures, and premature death. Mutations in CLN6 result in both a variant late infantile onset neuronal ceroid lipofuscinosis (vLINCL) as well as an adult-onset form of the disease called Type A Kufs. CLN6 is a non-glycosylated membrane protein of unknown function localized to the endoplasmic reticulum (ER). In this study, we perform a detailed characterization of a naturally occurring Cln6 mutant (Cln6(nclf)) mouse line to validate its utility for translational research. We demonstrate that this Cln6(nclf) mutation leads to deficits in motor coordination, vision, memory, and learning. Pathologically, we demonstrate loss of neurons within specific subregions and lamina of the cortex that correlate to behavioral phenotypes. As in other NCL models, this model displays selective loss of GABAergic interneuron sub-populations in the cortex and the hippocampus with profound, early-onset glial activation. Finally, we demonstrate a novel deficit in memory and learning, including a dramatic reduction in dendritic spine density in the cerebral cortex, which suggests a reduction in synaptic strength following disruption in CLN6. Together, these findings highlight the behavioral and pathological similarities between the Cln6(nclf) mouse model and human NCL patients, validating this model as a reliable format for screening potential therapeutics.

Show MeSH
Related in: MedlinePlus