Abnormal expression of synaptic proteins and neurotrophin-3 in the Down syndrome mouse model Ts65Dn

Abstract

Down syndrome (DS) results from triplication of the whole or distal part of human chromosome 21. Persons with DS suffer from deficits in learning and memory and cognitive functions in general, and, starting from early development, their brains show dendritic and spine structural alterations and cell loss. These defects concern many cortical brain regions as well as the hippocampus, which is known to play a critical role in memory and cognition. Most of these abnormalities are reproduced in the mouse model Ts65Dn, which is partially trisomic for the mouse chromosome 16 that is homologous to a portion of human chromosome 21. Thus, Ts65Dn is widely utilized as an animal model of DS. To better understand the molecular defects underlying the cognitive and particularly the memory impairments of DS, we investigated whether the expression of several molecules known to play critical roles in long-term synaptic plasticity and long-term memory in a variety of species is dysregulated in either the neonatal brain or adult hippocampus of Ts65Dn mice. We found abnormal expression of the synaptic proteins synaptophysin, microtubule-associated protein 2 (MAP2) and cyclin-dependent kinase 5 (CDK5) and of the neurotrophin-3 (NT-3). Both the neonatal brain and adult hippocampus revealed significant abnormalities. These results suggest that a dysregulation in the expression of neurotrophins as well as proteins involved in synaptic development and plasticity may play a potential role in the neural pathology of DS in humans.

Fig. 1

Representative examples and quantitative densitometric analyses of western blot of extracts from 1-day-old (neonatal brain) Ts65Dn whole brain and littermate age-matched controls. Protein levels were normalized using actin or nuclear pore complex protein to account for differences in loading. Data are expressed as mean percentage ±SEM of the littermate control mean values. (a) MAP2 is significantly increased in neonatal day 1 Ts65Dn. (b) NT-3 is significantly increased in neonatal day 1 Ts65Dn.

Fig. 2

Representative examples and quantitative densitometric analysis of western blot of extracts from hippocampi of 4-month-old Ts65Dn (adult hippocampus) and those of littermate age-matched controls. Protein levels were normalized using actin to account for differences in loading. Data are expressed as mean percentage ±SEM of the littermate control mean values. (a) Synaptophysin is significantly decreased in Ts65Dn hippocampi. (b) NT-3 is significantly increased in Ts65Dn hippocampi. (c) CDK5 is significantly increased in the hippocampi of Ts65Dn.