Protein Dynamics Associated with Failed and Rescued Learning in the Ts65Dn Mouse Model of Down Syndrome

Abstract

Down syndrome (DS) is caused by an extra copy of human chromosome 21 (Hsa21). Although it is the most common genetic cause of intellectual disability (ID), there are, as yet, no effective pharmacotherapies. The Ts65Dn mouse model of DS is trisomic for orthologs of ∼55% of Hsa21 classical protein coding genes. These mice display many features relevant to those seen in DS, including deficits in learning and memory (L/M) tasks requiring a functional hippocampus. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist, memantine, was shown to rescue performance of the Ts65Dn in several L/M tasks. These studies, however, have not been accompanied by molecular analyses. In previous work, we described changes in protein expression induced in hippocampus and cortex in control mice after exposure to context fear conditioning (CFC), with and without memantine treatment. Here, we extend this analysis to Ts65Dn mice, measuring levels of 85 proteins/protein modifications, including components of MAP kinase and MTOR pathways, and subunits of NMDA receptors, in cortex and hippocampus of Ts65Dn mice after failed learning in CFC and after learning was rescued by memantine. We show that, compared with wild type littermate controls, (i) of the dynamic responses seen in control mice in normal learning, >40% also occur in Ts65Dn in failed learning or are compensated by baseline abnormalities, and thus are considered necessary but not sufficient for successful learning, and (ii) treatment with memantine does not in general normalize the initial protein levels but instead induces direct and indirect responses in approximately half the proteins measured and results in normalization of the endpoint protein levels. Together, these datasets provide a first view of the complexities associated with pharmacological rescue of learning in the Ts65Dn. Extending such studies to additional drugs and mouse models of DS will aid in identifying pharmacotherapies for effective clinical trials.

Exploring high-dimensional biological data with sparse contrastive principal component analysis

“…Down Syndrome, the leading genetic cause of intellectual disability [7], is the result of trisomy of all or part of the long arm of chromosome 21 [2]. Recently, researchers have begun exploring the use of pharmacotherapies to mitigate these cognitive deficits using the Ts65Dn mouse model [2,6]. Though not a perfect model for the study of Down Syndrome, the Ts65Dn displays many relevant neurological phenotypic features, such as deficits in learning and memory [12].…”

“…Ahmed et al [2] analyzed protein expression in the hippocampus and cortex of Ts65Dn and control mice after exposure to context fear conditioning and Memantine treatment. Memantine, a drug often prescribed to Alzheimer's patients, has been demonstrated to improve performance of the Ts65Dn in tasks that reflect cognitive abilities [2]. The corresponding dataset was made available by Higuera et al [6].…”

Deep feature selection for Identification of Essential Proteins of Learning and Memory in Mouse Model of Down Syndrome

“…Down syndrome (DS) is one of the most prominent causes of memory and learning hour and some minutes), or the region and method of the protein analysis [14]. For 22 instance, Ahmed et al [14] used the reverse phase protein arrays (RPPA) to analyze the 23 levels of more than 80 proteins in mice exposed to Context Fear Conditioning (CFC) to 24 provide a study of protein responses and interactions after normal learning. Higuera at 25 el.…”

“…62 Table 1. Abbreviations used in the paper and its meaning In this study, we use a dataset of mice proteins expressions [14]. The dataset consists of 64 the expression levels of 77 proteins/protein modifications that produced detectable 65 signals in the nuclear fraction of the cortex.…”

“…Therefore, for control mice, there are 38x15, or 570 68 measurements, and for trisomic mice, there are 34x15, or 510 measurements. The 69 dataset contains a total of 1080 measurements per protein, and each measurement can 70 be considered as an independent sample [14]. Fig 2 shows the distribution of each mice 71 group in the dataset.…”