Loss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down's Syndrome

doi:10.1006/exnr.1999.7289

Experimental Neurology

Volume 161, Issue 2, February 2000, Pages 647-663

https://doi.org/10.1006/exnr.1999.7289 Get rights and content

Abstract

Mice with segmental trisomy of chromosome 16 (Ts65Dn) have been used as a model for Down's syndrome. These mice are born with a normal density of basal forebrain cholinergic neurons but, like patients with Down's syndrome, undergo a significant deterioration of these neurons later in life. The time course for this degeneration of cholinergic neurons has not been studied, nor is it known if it correlates with the progressive memory and learning deficits described. Ts65Dn mice that were 4, 6, 8, and 10 months old were sacrificed for evaluation of basal forebrain morphology. Separate groups of mice were tested on visual or spatial discrimination learning and reversal. We found no alterations in cholinergic markers in 4-month-old Ts65Dn mice, but thereafter a progressive decline in density of cholinergic neurons, as well as significant shrinkage of cell body size, was seen. A parallel loss of staining for the high-affinity nerve growth factor receptor, trkA, was observed at all time points, suggesting a biological mechanism for the cell loss involving this growth factor. Other than transient difficulty in learning the task requirements, there was no impairment of trisomic mice on visual discrimination learning and reversal, whereas spatial learning and reversal showed significant deficits, particularly in the mice over 6 months of age. Thus, the loss of ChAT-immunoreactive neurons in the basal forebrain was coupled with simultaneous deficits in behavioral flexibility on a spatial task occurring for the first time around 6 months of age. These findings suggest that the loss of cholinergic function and the simultaneous decrease in trkA immunoreactivity in basal forebrain may directly correlate with cognitive impairment in the Ts65Dn mouse

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Regular ArticleLoss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down's Syndrome

Abstract

Genomics

Exp. Neurol.

Brain Res.

Neuroscience

J. Psych. Res.

Brain Res. Bull.

TINS

Brain Res.

Neurobiol. Aging

Neurochem. Int.

Brain Res.

Neurosci. Lett.

Brain Res.

Brain Res.

Dev. Brain Res

Neurobiol. Aging

Neurosci. Lett.

Neurosci. Lett.

Brain Res. Mol. Brain Res.

Neuron

Exp. Neurol.

Biochem. Biophys. Res. Commun.

Neuroscience

Neurosci. Lett.

Brain Res

Neuropharmacology

Neurobiol. Aging

Brain Res.

Trk neurotrophin receptors in cholinergic neurons of patients with Alzheimer's disease

Dementia Geriatric Cog. Disord.

Systemic administration of a nerve growth factor conjugate reverses age-related cognitive dysfunction and prevents cholinergic neuron atrophy

J. Neurosci.

Abnormalities of the nucleus basalis in Down's syndrome

Ann. Neurol.

Nerve growth factor corrects developmental impairments of basal forebrain cholinergic neurons in the trisomy 16 mouse

Proc. Natl. Acad. Sci. USA

Down syndrome: Neuropsychology and animal models

Prog. Infancy Res.

Segmental trisomy of murine chromosome 16: A new model system for studying Down syndrome

Prog. Clin. Biol. Res.

Segmental trisomy as a mouse model for Down's syndrome

Prog. Clin. Biol. Res.

Regular Article
Loss of Cholinergic Phenotype in Basal Forebrain Coincides with Cognitive Decline in a Mouse Model of Down's Syndrome