Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons

Weimer, Jill M.; Custer, Andrew W.; Benedict, Jared W.; Alexander, Noreen A.; Kingsley, Evan P.; Federoff, Howard J.; Cooper, Jonathan D.; Pearce, David A.

doi:10.1016/j.nbd.2005.11.008

Cited by 67 publications

(60 citation statements)

References 38 publications

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“…Phenotypic analyses of the mouse gene knockout models indicate that the effects of Cln3 gene disruption in mice are generally less profound than they are in humans (Pontikis et al, 2004;Seigel et al, 2002;Weimer et al, 2006). For example, life expectancy in affected human subjects is reduced by about two-thirds, even with excellent medical care, whereas the mean life spans of the Cln3 -/-mice evaluated in this study are reduced by only 19% relative to control mice.…”

Section: Discussionmentioning

confidence: 67%

“…Retinal morphology has been studied in two other mouse models of JNCL (Cotman et al, 2002;Seigel et al, 2002;Weimer et al, 2006). Seigel and colleagues (Seigel et al, 2002) evaluated the effects of a Cln3 knockout mutation in the 129/SvEvTac (129S6) mouse strain.…”

Section: Discussionmentioning

confidence: 99%

“…Given the evidence of apoptosis among retinal cells in the 129S6 Cln3 -/-mice, it appears likely that modest losses of retinal neurons similar to those observed in the C57BL/6J Cln3 -/-model occurred in the 129S6 model. Weimer and colleagues also studied the retina in Cln3 -/-mice up to 12 months of age (Weimer et al, 2006). Based on their citation of the source of the mutant mice, they appeared have used the same model studied by Seigel and colleagues, although Weimer et al stated that in the mice they studied the mutation was on the 129/SvJ strain background.…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Katz

Johnson

Tullis

2008

Neurobiology of Disease

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Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessively inherited neurodegenerative disorder that results from mutations in the CLN3 gene. JNCL is characterized by accumulation of autofluorescent lysosomal storage bodies, vision loss, seizures, progressive cognitive and motor decline, and premature death. Studies were undertaken to characterize the neuronal ceroid lipofuscinosis phenotype in a Cln3 knockout mouse model. Progressive accumulation of autofluorescent storage material was observed in brain and retina of affected mice. The Cln3 -/-mice exhibited progressively impaired inner retinal function, altered pupillary light reflexes, losses of inner retinal neurons, and reduced brain mass. Behavioral changes included reduced spontaneous activity levels and impaired learning and memory. In addition, Cln3 -/-mice had significantly shortened life spans. These phenotypic features indicate that the mouse model will be useful for investigating the mechanisms underlying the disease pathology in JNCL and provide quantitative markers of disease pathology that can be used for evaluating the efficacies of therapeutic interventions.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Katz

Johnson

Tullis

2008

Neurobiology of Disease

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“…The discrepancy between the extent of photoreceptor loss in patients versus mouse models may reflect the shorter lifespan of the mouse. Alternatively, as suggested in a recent study (Weimer et al, 2006), loss of retinal neurons may be secondary to neuronal loss in visual centers, which differ between mouse and human. In Cln3 lacZ/lacZ mice, we clearly detect reporter expression in the retina.…”

Section: Discussionmentioning

confidence: 85%

A Knock-In Reporter Model of Batten Disease

Eliason¹,

Stein²,

Mao³

et al. 2007

J. Neurosci.

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Juvenile neuronal ceroid lipofuscinosis is a severe inherited neurodegenerative disease resulting from mutations in CLN3 (ceroidlipofuscinosis, neuronal 3, juvenile). CLN3 function, and where and when it is expressed during development, is not known. In this study, we generated a knock-in reporter mouse to elucidate CLN3 expression during embryogenesis and after birth and to correlate expression and behavior in a CLN3-deficient mouse. In embryonic brain, expression appeared in the cortical plate. In postnatal brain, expression was prominent in the cortex, subiculum, parasubiculum, granule neurons of the dentate gyrus, and some brainstem nuclei. In adult brain, reporter gene expression waned in most areas but remained in vascular endothelia and the dentate gyrus. Mice homozygous for Cln3 deletion showed two hallmark pathological features of the neuronal ceroid lipofuscinosises: autofluorescent inclusions and lysosomal enzyme elevation. Moreover, CLN3-deficient reporter mice displayed progressive neurological deficits, including impaired motor function, decreased overall activity, acquisition of resting tremors, and increased susceptibility to pentilentetrazole-induced seizures. Notably, seizure induction in heterozygous mice was accompanied by enhanced reporter expression. This model provides us with the unique ability to correlate expression with pathology and behavior, thus facilitating the elucidation of CLN3 function and the pathogenesis of Batten disease.

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“…LGNd neurons is evident in Cln3 deficient mice and may underlie the visual defects characteristic of JNCL (Weimer et al, 2006). Taken together these data suggest that the primary site of pathology in multiple forms of NCL is not within the retina itself, although effects upon the optic nerve itself cannot be excluded.…”

Section: The Thalamus As An Early Target In Inclmentioning

confidence: 87%

Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis

Kielar

Maddox

Bible

et al. 2007

Neurobiology of Disease

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161

275

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Infantile neuronal ceroid lipofuscinosis (INCL) is caused by deficiency of the lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1). We have investigated the onset and progression of pathological changes in Ppt1-deficient mice (Ppt1 −/− ) and the development of their seizure phenotype. Surprisingly, cortical atrophy and neuron loss occurred only late in disease progression, but were preceded by localized astrocytosis within individual thalamic nuclei and the progressive loss of thalamic neurons that relay different sensory modalities to the cortex. This thalamic neuron loss occurred first within the visual system and only subsequently in auditory and somatosensory relay nuclei or the inhibitory reticular thalamic nucleus. The loss of granule neurons and GABAergic interneurons followed in each corresponding cortical region, before the onset of seizure activity. These findings provide novel evidence for successive neuron loss within the thalamus and cortex in Ppt1 −/− mice, revealing the thalamus as an important early focus of INCL pathogenesis.

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Visual deficits in a mouse model of Batten disease are the result of optic nerve degeneration and loss of dorsal lateral geniculate thalamic neurons

Cited by 67 publications

References 38 publications

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

Phenotypic characterization of a mouse model of juvenile neuronal ceroid lipofuscinosis

A Knock-In Reporter Model of Batten Disease

Successive neuron loss in the thalamus and cortex in a mouse model of infantile neuronal ceroid lipofuscinosis

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