Browsing by Subject "Down Syndrome (DS)"

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    Can Epigallocatechin gallate (EGCG) Treatment Rescue Hippocampal-Dependent Cognitive Function in a Down Syndrome Mouse Model?
    (Office of the Vice Chancellor for Research, 2016-04-08) East, Audrey; Stringer, Megan; Abeysekera, Irushi; Goodlett, Charles R.; Roper, Randall J.
    Down Syndrome (DS) is caused by the trisomy of human chromosome 21 (Hsa21). Trisomy 21 can cause various behavioral, cognitive, learning and memory deficits. Deficits in hippocampal structure and function have been identified in mouse models of DS and are implicated in cognitive and learning impairments. Mouse models have suggested that deficits in cognitive function are associated with overexpression of Dyrk1a, a gene on Hsa21 found in three copies of individuals with DS. Dyrk1a is a gene that is involved in brain development and function. Ts65Dn DS model mice exhibit trisomy for approximately half of the genes on Hsa21 including Dyrk1a and exhibit cognitive and learning impairments. We are using Ts65Dn mice to test the effects of Epigallocatechin gallate (EGCG), a Dyrk1a inhibitor, on Dyrk1a activity and cognitive function. We hypothesize that EGCG will reduce Dyrk1a activity in the hippocampus and improve hippocampal-dependent spatial learning and memory in the Morris water maze place learning task in Ts65Dn mice. The mice were given daily EGCG treatment (200 mg/kg per day) by means of oral gavage beginning on postnatal day 54 and continuing throughout water maze testing (postnatal days 67-74). Measures of spatial learning included latency and path length to find a submerged platform during acquisition trials (postnatal days 67-73). Memory for the previously learned location of the platform was assessed on a probe trial (postnatal day 74) in which the platform was removed and the amount of time spent swimming in the area of the tank previously containing the platform was measured. These measures allowed us to analyze the mice’s ability to learn and remember the position of the platform and to spatially orient themselves. Preliminary data indicates that EGCG treatment may not be an effective treatment for the spatial learning and memory deficits evident in this mouse model of DS.
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    Effects of the Calcineurin/NFAT Pathway in Skeletal Abnormalities Associated with Down Syndrome
    (Office of the Vice Chancellor for Research, 2015-04-17) Thomas, Jared; Patel, Rushiv; Roper, Randall J.
    Down Syndrome (DS) is a genetic disorder caused by trisomy of human chromosome 21 (Hsa21). DS phenotypes include cognitive impairment, craniofacial abnormalities, and skeletal deficiencies. The Ts65Dn mouse model exhibits similar phenotypes as found in humans with DS, including deficits in skeletal bone. Over-expression of DYRK1A, a serine-threonine kinase encoded on Hsa21, has been linked to deficiencies in DS bone homeostasis. Calcineruin/NFAT pathway plays a role in bone homeostasis by regulating osteoblastogenesis and osteoclastogenesis. DYRK1A was found to regulate calcineruin/NFAT signaling to block transcriptional activity, thereby reducing calcineruin/NFAT transcriptional activity. Epigallocatechin-3-gallate (EGCG), an aromatic polyphenol found in green tea, is a known inhibitor of DYRK1A activity. Normalization of DYRK1A activity by EGCG may have the potential to regulate bone homeostasis, by increasing bone mineral density (BMD) and bone strength. In earlier our work, EGCG treatment of 30mg/kg/day, has been shown to improve skeletal deficits, however, the mechanism remains unknown. We hypothesize that EGCG is involved in the calcineurin/NFAT pathway. To test our hypothesis we will use cyclosporine A (CsA), an immunosuppressant that perturbs the calcineurin/NFAT pathway. Previous studies show that daily administration of high concentration CsA will result in significant bone loss. Three-week old euploid and trisomic Ts65Dn mice receive 30mg/kg/day of CsA or vehicle for 3 weeks. In addition, mice will receive EGCG or water. At six weeks of age, BMD, bone strength, as well as architecture of the cortical and trabecular bone are assessed in extracted femurs. We expect that CsA given to euploid mice exhibit bone phenotypes similar to trisomic mice. Whereas euploid mice given CsA and EGCG might display bone phenotypes similar to euploid given only the vehicle. Provided that we are able to observe our expected results, it may indicate that EGCG is involved in the calcineurin/NFAT pathway. Our work is important to understand how EGCG may affect DS phenotypes as the EGCG is translated to human use.
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    Evaluation of osteoclastogenesis in the Ts65Dn Down Syndrome Mouse Model
    (Office of the Vice Chancellor for Research, 2015-04-17) Abeysekera, Irushi S.; Raje, Kimaya; Roper, Randall J.
    Down Syndrome (DS) affects ~1 in 700 live births and is caused by trisomy of human chromosome 21 (Hsa21). DS is characterized by a wide spectrum of phenotypes including cognitive and skeletal abnormalities that affect all individuals with DS. To study these phenotypes, we utilize the Ts65Dn mouse model, which contains three copies of approximately half the gene orthologous found on Hsa21 and exhibits similar phenotypes as found in humans with DS. Individuals with DS and Ts65Dn mice have deficits in bone mineral density (BMD), bone architecture, and bone strength. Three copies of DYRK1A, a serine-threonine kinase encoded on Hsa21, has been linked to deficiencies in bone homeostasis in DS mouse models and individuals with DS. DYRK1A is thought to act via NFATc1, a master regulator of osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), a polyphenol found in high concentrations in green tea, is a known inhibitor of DYRK1A activity. We propose that the DS bone phenotype arises from an increase in osteoclastogenesis and/or maturation which results in increased bone resorption and disrupted bone homeostasis. We hypothesize that treatment of the mice during adolescence with 100 mg/kg/day EGCG would result in normalization of osteoclast numbers in trisomic mice to that of the controls. Osteoclast precursors from femur and spleen were isolated from 8-10 week old mice treated with 100 mg/kg/day EGCG or water from three weeks of age onwards. The cells were grown in the presence of M-CSF & RANK-L to promote osteoclast differentiation. Following 3 weeks in culture, the cells were fixed, TRAP stained, and multinucleated osteoclasts from control and Ts65Dn treated and untreated mice were counted. Mentor: Randall Roper, Department of Biology, IUPUI School of Science, Indianapolis, IN
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    Multivariate Concentric Square Field unveils behavioral exploratory categories of locomotor activity in mouse model of Down syndrome
    (Office of the Vice Chancellor for Research, 2015-04-17) Stancombe, Kailey E.; Goodlett, Charles R.; Stewart, Robert J.; Stringer, Megan; Roper, Randall J.
    Down Syndrome (DS), trisomy 21(Ts21), is a genetic condition in which a third copy of chromosome 21 is present, and results in neurodevelopmental deficits including intellectual disability. DS has been modeled in mice; Ts65Dn mouse model displays many of the phenotypes associated with DS, including cognitive deficits. We previously studied behavioral phenotypes of Ts65Dn mice and observed significantly increased locomotor activity in a novel arena (an “open field”). In those studies, treatment of the Ts65Dn mice with ~10 mg/kg/day of epigallocatechin-3-gallate (EGCG), a selective inhibitor of the DYRK1A kinase (one of the genes implicated in the neurodevelopmental deficits in DS and in Ts65Dn mice), failed to attenuate hyperactivity. Locomotor activity in an open field is a basic measure of general exploration in a simple environment, and was only moderately sensitive to the hyperactivity of the Ts65Dn mice. The aim of the current study was to use a more advanced analysis of behavioral patterns of exploration in a more complex, multi-partitioned arena, termed the Multivariate Concentric Square Field (MCSF). The advantage of MCSF is that it provides more elaborate measures of exploratory behavior by examining different categories of exploration: general activity, exploratory activity, risk assessment, risk taking and shelter seeking behavior. Trisomic mice and euploid littermates were treated with a continuous high dose (~100 mg/kg/day) of EGCG or water (controls) beginning at weaning. At seven weeks of age, they were tested in the MCSF on two consecutive days. Our current results indicate that Ts65Dn mice displayed more exploratory behavior compared to controls, and the EGCG treatment may have normalized exploratory behavior toward that of controls. Identifying altered patterns of exploratory behavior in the Ts65Dn mouse and the normalizing effects of EGCG treatment may help provide a therapeutic approach to DS.