title: 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.
authors: Linda Crnic Institute for Down Syndrome, Department of Pediatrics, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America.
authors: Md Mahiuddin
authors: MM
authors: Ahmed
authors: Linda Crnic Institute for Down Syndrome, Department of Pediatrics, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America.
authors: A Ranjitha
authors: AR
authors: Dhanasekaran
authors: Linda Crnic Institute for Down Syndrome, Department of Pediatrics, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America.
authors: Aaron
authors: A
authors: Block
authors: Colorado School of Public Health, University of Colorado Denver, Mail Stop A036-B065 TCH, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America.
authors: Suhong
authors: S
authors: Tong
authors: Division of Pediatric Neurology, Mail Stop RBC 6090, Department of Pediatrics, Case Western Reserve School of Medicine, Rainbow Babies & Children's Hospital, 11100 Euclid Avenue, Cleveland, OH 44106-6090, United States of America.
authors: Alberto C S
authors: AC
authors: Costa
authors: Division of Pediatric Neurology, Mail Stop RBC 6090, Department of Pediatrics, Case Western Reserve School of Medicine, Rainbow Babies & Children's Hospital, 11100 Euclid Avenue, Cleveland, OH 44106-6090, United States of America.
authors: Melissa
authors: M
authors: Stasko
authors: Linda Crnic Institute for Down Syndrome, Department of Pediatrics, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America; Department of Biochemistry and Molecular Genetics, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America; Human Medical Genetics and Genomics, and Neuroscience Programs, University of Colorado Denver, Mail Stop 8608, 12700 E 19th Avenue, Aurora, Colorado 80045, United States of America.
authors: Katheleen J
authors: KJ
authors: Gardiner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D007858:Learning / Q000187:drug effects; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D021122:Protein Subunits / Q000378:metabolism; D020543:Proteome; D040901:Proteomics / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism
chemical_list: D021122:Protein Subunits; D020543:Proteome; D016194:Receptors, N-Methyl-D-Aspartate; D008559:Memantine