| 2001 — 2003 |
Galdzicki, Zygmunt |
R01Activity Code Description:
To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Mouse Model of Retardation in Downs Syndrome @ Henry M. Jackson Fdn For the Adv Mil/Med
DESCRIPTION (Provided by applicant): 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.
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0.913 |
| 2011 — 2015 |
Galdzicki, Zygmunt
Haydar, Tarik F [⬀] |
R01Activity Code Description:
To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Rescue of Forebrain Defects in Mouse Models of Down Syndrome @ Boston University Medical Campus
DESCRIPTION (provided by applicant): Down syndrome (DS), or Trisomy 21, is the most common genetic cause of cognitive disability, afflicting 1 in every 800 live births. Importantly, the cause(s) of the cognitive disability in DS have not yet been uncovered. Our group has been studying the Ts65Dn mouse model of DS which has triplication of 184 of the 364 genes triplicated in DS. These mice have a large number of DS- relevant phenotypes, including cardiac and craniofacial defects as well as spatial learning/memory and motor abnormalities, the latter two of which have been principally measured in adult animals. We now report two major developmental forebrain phenotypes in Ts65Dn which precede these neurological deficits: 1) a dorsal forebrain abnormality which results in under-production of excitatory neurons and 2) a ventral forebrain defect which results in over-production of inhibitory interneurons. Together, these defects substantially shift the excitatory:inhibitory neuron ratio in Ts65Dn;we hypothesize that this is the primary cause for cognitive dysfunction in Ts65Dn/DS. Through a comprehensive set of experiments on cell proliferation, neural differentiation, gene expression and neuronal electrophysiology, we uncovered that two specific triplicated genes (the structurally linked transcription factors Olig1 and Olig2) cause the ventral Ts65Dn forebrain phenotype;we rescued the inhibitory defect in the embryonic and adult brain at the cellular and electrophysiological levels by generating Ts65DnOlig1/2? animals (reducing Olig1 and Olig2 genes from 3 to 2 alleles within the Ts65Dn background). In this period of study, we will determine whether Olig1/2 triplication influences the learning/memory and synaptic plasticity defects in Ts65Dn and investigate the role of the Dyrk1a minibrain gene in the (dorsal) excitatory neuron deficit in Ts65Dn. PUBLIC HEALTH RELEVANCE: Down syndrome is the most common genetic disorder resulting in mental retardation and it afflicts approximately 384,000 Americans (1:800). As such, the development of therapies for cognitive ability is critical for improving quality of life of patients and their families. In this project, we are discovering which triplicated genes lead to altered brain development and function in the Ts65Dn mouse model of Down syndrome. By reducing the dosage of three triplicated genes implicated in early brain development, this work will identify the gene targets, describe how their over-expression changes brain development and lead to prenatal and postnatal strategies for cognitive therapy.
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0.925 |