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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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Cortical atrophy limited in Cln6nclf mice.Cortical thickness was evaluated in age matched WT and Cln6nclf mice. (A) In the S1BF, thinning begins to appear at 6 months. (B) Thinning in the M1 region is seen at 11 months. (C) Cortical thickness was unchanged in the LEnt (C) region of the cerebral cortex. (D–E) The S1BF (D) and M1 (E) regions were analyzed for possible laminar specific atrophy. Thinning is seen in lamina V of the M1 region at 11 months as well as an apparent thickening in lamina IV. Thinning is seen in the S1BF region in lamina VI at 6 months. [Mean +/− SEM (n = 3,*p≤0.05, **p≤0.01)].
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pone-0078694-g004: Cortical atrophy limited in Cln6nclf mice.Cortical thickness was evaluated in age matched WT and Cln6nclf mice. (A) In the S1BF, thinning begins to appear at 6 months. (B) Thinning in the M1 region is seen at 11 months. (C) Cortical thickness was unchanged in the LEnt (C) region of the cerebral cortex. (D–E) The S1BF (D) and M1 (E) regions were analyzed for possible laminar specific atrophy. Thinning is seen in lamina V of the M1 region at 11 months as well as an apparent thickening in lamina IV. Thinning is seen in the S1BF region in lamina VI at 6 months. [Mean +/− SEM (n = 3,*p≤0.05, **p≤0.01)].

Mentions: Cortical atrophy, specifically in the primary motor (M1) and somatosensory barrel field (S1BF) cortex, has been widely reported in NCL animal models [26], [47], [52], [57], [58]. Therefore, we next examined Cln6nclf mice for signs of cortical atrophy and observed a significant loss of brain mass at 5 months and further decreased by 9 months, while the overall weight of the mice remained unchanged (Fig. 3 A, C). Atrophy was prominent in the cerebral cortex, with a reduction in volume seen in the neocortex at 9 months (Fig. 3 B). To discern which subregions of the cerebral cortex where affected, we measured thickness of the S1BF, M1, and lateral entorhinal (LEnt) (Fig. 4 A–C) cortex. Cortical atrophy appeared to be restricted to the S1BF and M1 regions, with an 8% reduction in S1BF cortical thickness at 6 months and a 10% reduction in M1 by 11 months (Fig. 4 A–B).


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)

Cortical atrophy limited in Cln6nclf mice.Cortical thickness was evaluated in age matched WT and Cln6nclf mice. (A) In the S1BF, thinning begins to appear at 6 months. (B) Thinning in the M1 region is seen at 11 months. (C) Cortical thickness was unchanged in the LEnt (C) region of the cerebral cortex. (D–E) The S1BF (D) and M1 (E) regions were analyzed for possible laminar specific atrophy. Thinning is seen in lamina V of the M1 region at 11 months as well as an apparent thickening in lamina IV. Thinning is seen in the S1BF region in lamina VI at 6 months. [Mean +/− SEM (n = 3,*p≤0.05, **p≤0.01)].
© Copyright Policy
Related In: Results  -  Collection

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

pone-0078694-g004: Cortical atrophy limited in Cln6nclf mice.Cortical thickness was evaluated in age matched WT and Cln6nclf mice. (A) In the S1BF, thinning begins to appear at 6 months. (B) Thinning in the M1 region is seen at 11 months. (C) Cortical thickness was unchanged in the LEnt (C) region of the cerebral cortex. (D–E) The S1BF (D) and M1 (E) regions were analyzed for possible laminar specific atrophy. Thinning is seen in lamina V of the M1 region at 11 months as well as an apparent thickening in lamina IV. Thinning is seen in the S1BF region in lamina VI at 6 months. [Mean +/− SEM (n = 3,*p≤0.05, **p≤0.01)].
Mentions: Cortical atrophy, specifically in the primary motor (M1) and somatosensory barrel field (S1BF) cortex, has been widely reported in NCL animal models [26], [47], [52], [57], [58]. Therefore, we next examined Cln6nclf mice for signs of cortical atrophy and observed a significant loss of brain mass at 5 months and further decreased by 9 months, while the overall weight of the mice remained unchanged (Fig. 3 A, C). Atrophy was prominent in the cerebral cortex, with a reduction in volume seen in the neocortex at 9 months (Fig. 3 B). To discern which subregions of the cerebral cortex where affected, we measured thickness of the S1BF, M1, and lateral entorhinal (LEnt) (Fig. 4 A–C) cortex. Cortical atrophy appeared to be restricted to the S1BF and M1 regions, with an 8% reduction in S1BF cortical thickness at 6 months and a 10% reduction in M1 by 11 months (Fig. 4 A–B).

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