The long-term goal of this project is to use mouse models to assess the potential clinical application of various pharmacological agents to the therapy of the mental deficit associated with Down syndrome (DS). Ts65Dn mice are the prime animal model for mental retardation in DS. These mice are trisomic for a chromosomal segment homologous to a large portion of human Chromosome 21 and display significant learning deficits in specific behavioral tests. Presently, there are two major factors limiting their widespread use in pre-clinical therapeutic trials: 1) poorly characterized neurological phenotype, which limits the scope of any pharmacological study; 2) low fertility rate, which curbs large- scale production. This project will address these limitations and systematically evaluate the efficacy of a series of 8 pharmacological agents in preventing and/or reversing learning deficits and DS-like neurological signs expressed by Ts65Dn mice. Each agent belongs to a different class of compounds for which there is a reasonable consensus about possible mechanisms of action in the central nervous system (CNS). Therefore, the investigation of their effect on Ts65Dn mice will be also a test for specific hypotheses about the pathophysiology of DS. To accomplish these goals, I propose 3 specific aims: 1) Evaluate the efficacy of 8 candidate therapeutic agents in preventing and/or reversing the learning deficit and DS-like neurological signs expressed by Ts65Dn mice; 2) Further investigate the neurological phenotype of Ts65Dn mice; 3) Use of in vitro fertilization techniques to test 4 key genetic issues related to Ts65Dn mice and to increase their availability.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
1R01HD037424-01
Application #
2825096
Study Section
Special Emphasis Panel (ZHD1-MRG-C (07))
Program Officer
Oster-Granite, Mary Lou
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Costa, Alberto C S (2011) An assessment of optokinetic nystagmus (OKN) in persons with Down syndrome. Exp Brain Res 214:381-91
Costa, Alberto C S (2011) An assessment of the vestibulo-ocular reflex (VOR) in persons with Down syndrome. Exp Brain Res 214:199-213
Scott-McKean, Jonah J; Wenger, Galen R; Tecott, Laurence H et al. (2008) 5-HT(1A) Receptor Null Mutant Mice Responding Under a Differential-Reinforcement-of-Low-Rate 72-Second Schedule of Reinforcement. Open Neuropsychopharmacol J 1:24-32
Stasko, Melissa R; Scott-McKean, Jonah J; Costa, Alberto C S (2006) Hypothermic responses to 8-OH-DPAT in the Ts65Dn mouse model of Down syndrome. Neuroreport 17:837-41
Costa, Alberto C S; Stasko, Melissa R; Stoffel, Markus et al. (2005) G-protein-gated potassium (GIRK) channels containing the GIRK2 subunit are control hubs for pharmacologically induced hypothermic responses. J Neurosci 25:7801-4
Costa, Alberto C S; Grybko, Michael J (2005) Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome. Neurosci Lett 382:317-22
Hampton, Thomas G; Stasko, Melissa R; Kale, Ajit et al. (2004) Gait dynamics in trisomic mice: quantitative neurological traits of Down syndrome. Physiol Behav 82:381-9
Stasko, Melissa R; Costa, Alberto C S (2004) Experimental parameters affecting the Morris water maze performance of a mouse model of Down syndrome. Behav Brain Res 154:1-17
Costa, A C; Walsh, K; Davisson, M T (1999) Motor dysfunction in a mouse model for Down syndrome. Physiol Behav 68:211-20