Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome

Abstract

Mouse models have provided insights into adult changes in learning and memory in Down syndrome, but an in-depth assessment of how these abnormalities develop over time has never been conducted. To address this shortcoming, we conducted a longitudinal behavioral study from birth until late adulthood in the Ts65Dn mouse model to measure the emergence and continuity of learning and memory deficits in individuals with a broad array of tests. Our results demonstrate for the first time that the pace at which neonatal and perinatal milestones are acquired is correlated with later cognitive performance as an adult. In addition, we find that lifelong behavioral indexing stratifies mice within each genotype. Our expanded assessment reveals that diminished cognitive flexibility, as measured by reversal learning, is the most robust learning and memory impairment in both young and old Ts65Dn mice. Moreover, we find that reversal learning degrades with age and is therefore a useful biomarker for studying age-related decline in cognitive ability. Altogether, our results indicate that preclinical studies aiming to restore cognitive function in Ts65Dn should target both neonatal milestones and reversal learning in adulthood. Here we provide the quantitative framework for this type of approach.

Early neurotrophic pharmacotherapy rescues developmental delay and Alzheimer’s-like memory deficits in the Ts65Dn mouse model of Down syndrome

“…Our data are congruent with previous studies that have demonstrated delay in the acquisition of developmental milestones during the early postnatal period in Ts65Dn mice1821141. Like DS infants, the Ts65Dn mice ultimately achieve developmental milestones but with significant delay as compared to their WT littermates.…”

“…A recent study reported a relationship between early motor skills and executive function in DS145. Similarly, in Ts65Dn mice, a positive correlation was recently reported between acquisition of developmental milestones during early postnatal period and cognitive performance in adult life141. The present study showed that prenatal to early postnatal treatment with P021 rescues the delay in some of the motor and sensory developmental milestones.…”

“…It was not possible for us to do a correlation analysis between acquisition of developmental milestones during the first 3 weeks of life and cognitive performance at adult stage as the data were collected from two separate batches of mice. Nonetheless, based on recent literature on Ts65Dn mice141, we speculate that at least one of the contributory factor in improved learning and memory performance in adult life in P021 treated Ts65Dn mice might be the amelioration of developmental delay during early postnatal period.…”

Alterations of specific inhibitory circuits of the prefrontal cortex underlie abnormal network activity in a mouse model of Down syndrome

“…Individuals with DS present important deficits in cognitive tasks known to depend on the anatomical and functional integrity of the frontal lobe 2 . Importantly, mouse models of DS recapitulate 55 several cognitive deficits of this condition 3,4 .…”

Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

“…Therefore, dendritic hypotrophy is very likely a second key determinant underlying the poor performance of individuals with DS in many cognitive domains. In addition, the axons of trisomic neurons have a reduced myelination, 7 which implies slower conduction of the action potentials and further impairment in the cross talk among neurons.…”