Abstract

Down syndrome (DS) or trisomy 21 (Ts21) is caused by the presence of three copies of chromosome 21, and is the most frequent genetic cause of mental retardation. The Ts65Dn trisomic mouse has recently been developed and is trisomic only for the segment of murine chromosome 16 that is homologous to the segment of human chromosome 21 thought to contribute to mental retardation and vulnerability to Alzheimer disease in DS. This mouse demonstrates abnormal behavior and is impaired in various learning paradigms. We demonstrated that long-term potentiation (LTP) and long- term depression (LTD) decrease and increase respectively in the CAl region of the Ts65Dn mouse of Ts65Dn mouse hippocampus. The objective of this proposal is to find mechanisms that cause the abnormal LTP and LTD.
Three specific aims are proposed to test that abnormal LTP and LTD are due to changes in signal transduction pathways mediated by protein kinase A (PKA) and/or protein kinase C (PKC) that would cause posttranslational changes in voltage-dependent Na+, Ca2+ channels and NMDA-, AMPA-glutamate receptors and cause changes in synaptic activity in the hippocampus.
Aim#1 : Determine PKA pathway activity in Ts65Dn hippocampus in relation to LTP and LTD paradigm. Determine expression of phosphorylated CREB.
Aim #2 :PKC activity in Ts65Dn hippocampus in relation to LTP and LTD paradigm. Determine expression pattern of PKC isoforms.
Aim #3 :Determine the expression and posttranslational modification of voltage dependent Na+, Ca2+ channels and NMDA -, AMPA- glutamate receptors using nucleated patch-clamp recording technique and binding studies. The impact of PKC isoforms will be tested in cell lines that permanently over express Na+ channel, Ca2+ channels, NMDA and AMPA receptors. Signal transduction impairments in genetic model of DS will determine important targets for treatment of mental retardation. In addition the outcome of this research will include further understanding of the role of PKA and PKC and voltage-dependent channels and NMDA- and AMPA-receptors in the mechanisms that are behind LTP and LTD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038417-02
Application #
6521277
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Oster-Granite, Mary Lou
Project Start
2001-04-01
Project End
2004-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
2
Fiscal Year
2002
Total Cost
$232,114
Indirect Cost

  Institution

Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817

  Publications

Best, Tyler K; Cramer, Nathan P; Chakrabarti, Lina et al. (2012) Dysfunctional hippocampal inhibition in the Ts65Dn mouse model of Down syndrome. Exp Neurol 233:749-57
Best, Tyler K; Cho-Clark, Madelaine; Siarey, Richard J et al. (2008) Speeding of miniature excitatory post-synaptic currents in Ts65Dn cultured hippocampal neurons. Neurosci Lett 438:356-61
Olson, Lisa E; Roper, Randall J; Sengstaken, Crystal L et al. (2007) Trisomy for the Down syndrome 'critical region'is necessary but not sufficient for brain phenotypes of trisomic mice. Hum Mol Genet 16:774-82
Best, Tyler K; Siarey, Richard J; Galdzicki, Zygmunt (2007) Ts65Dn, a mouse model of Down syndrome, exhibits increased GABAB-induced potassium current. J Neurophysiol 97:892-900
Harashima, Chie; Jacobowitz, David M; Stoffel, Markus et al. (2006) Elevated expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in cerebellar unipolar brush cells of a Down syndrome mouse model. Cell Mol Neurobiol 26:719-34
Siarey, Richard J; Kline-Burgess, Angelina; Cho, Madelaine et al. (2006) Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome. J Neurochem 98:1266-77
Harashima, Chie; Jacobowitz, David M; Witta, Jassir et al. (2006) Abnormal expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in hippocampus, frontal cortex, and substantia nigra of Ts65Dn mouse: a model of Down syndrome. J Comp Neurol 494:815-33
Siarey, Richard J; Villar, Angela J; Epstein, Charles J et al. (2005) Abnormal synaptic plasticity in the Ts1Cje segmental trisomy 16 mouse model of Down syndrome. Neuropharmacology 49:122-8
Galdzicki, Z; Siarey, R J (2003) Understanding mental retardation in Down's syndrome using trisomy 16 mouse models. Genes Brain Behav 2:167-78
Galdzicki, Z; Siarey, R; Pearce, R et al. (2001) On the cause of mental retardation in Down syndrome: extrapolation from full and segmental trisomy 16 mouse models. Brain Res Brain Res Rev 35:115-45