Browsing by Author "Patel, Roshni"

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    Correction of cerebellar movement related deficits by normalizing Dyrk1a copy number in the Ts65Dn mouse model for Down syndrome
    (Office of the Vice Chancellor for Research, 2016-04-08) Patel, Roshni; Stringer, Megan; Abeysekera, Irushi; Roper, Randall J.; Goodlett, Charles R.
    Elucidation of the underlying mechanisms involved in brain related deficits of Down syndrome (DS) would be useful for consideration of therapeutic interventions. Several DSspecific phenotypes have been hypothesized to be linked to altered expression or function of specific trisomic genes. One such gene of interest is D YRK1A , which has been implicated in behavioral functions of the hippocampus and cerebellum. The Ts65Dn mouse model for DS includes a triplication of D yrk1a in addition to a triplication of >100 other human chromosome 21 mouse orthologs. To evaluate the role of D yrk1a in cerebellar function, we have genetically normalized the D yrk1a copy number in otherwise trisomicTs65Dn mice and reduced D yrk1a copy number in otherwise euploid mice (2N) for a total of 3 alternative genetic doses of D yrk1a: EuploidDyrk1a +/+ , EuploidDyrk1a +/, Ts65DnDyrk1a +/+/+ , and Ts65DnDyrk1a +/+/. Cerebellar movementrelated function in these knockdown models is being assessed through a novel behavioral balance beam task. Additionally, levels of D yrk1a activity in the cerebellum for all genotypes were analyzed by HPLC. We have previously demonstrated that Ts65DnDyrk1a +/+/+ mice perform worse in the balance beam task in comparison to EuploidDyrk1a +/+ mice. Preliminary results of the current study do not indicate such a difference among Ts65DnDyrk1a +/+/+ mice in comparison to EuploidDyrk1a +/+ mice. We hypothesize that the lack of replication of the previous findings may be due to differences in postweaning housing environments. Mice in the previous study were singlehoused, whereas mice in the present study were grouphoused, which may help mitigate motor deficits in the trisomic mice. Additionally, current trends display a deficit in balance beam performance of both the EuploidDyrk1a +/and the Ts65DnDyrk1a +/+/groups, which suggests that reducing the copy number of D yrk1a by one may have detrimental effects on motor coordination. Concomitant analysis of the balance beam performances and Dyrk1a activity levels may indicate the sensitivity of the balance beam task to assess the role Dyrk1a activity in cerebellar function.
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    The Effect of 200mg/kg EGCG Oral Gavage Treatment on the Cerebellar-Dependent Behavior in a Down Syndrome Mouse Model
    (Office of the Vice Chancellor for Research, 2016-04-08) Dalman, Noriel; Stringer, Megan; Abeysekera, Irushi; East, Audrey; Patel, Roshni; Roper, Randall J.; Goodlett, Charles R.
    Trisomy 21 (Ts21) causes deficits in motor and cognitive ability that are hallmark phenotypes in Down syndrome (DS). The Ts65Dn mouse model of DS has about 50% of the orthologous genes that are triplicated from human chromosome 21, including the Dual specificity tyrosinephosphorylation-regulated kinase 1A (Dyrk1A) gene. Three copies of Dyrk1A have been implicated in the motor and cognitive deficits and altered cerebellar structure and function may contribute these impairments in Ts65Dn mice. Epigallocatechin 3-gallate (EGCG) is a catechin found in green tea and an inhibitor of Dyrk1A activity. We hypothesize that a 200mg/kg EGCG treatment given by oral gavage will inhibit Dyrk1A activity in the cerebellum of Ts65Dn mice and rescue deficits in motor coordination while performing the balance beam task. Evidence of improvement in this task would be observed as a reduction of paw slips as the animal traverses across beams of varying widths. In previous studies, EGCG treatment was placed in the animal’s water to be consumed but EGCG rapidly degrades in solution and it is difficult to control treatment doses via treatment in drinking water, due to each animal’s consumption behavior. This study utilized a daily oral gavage treatment of EGCG to control the dose and limits loss due to degradation. Results to date indicate that the Ts65Dn mice show deficits on the balance beam task relative to the euploid mice, particularly at the narrowest beam width used. The EGCG treatment does not appear to improve the performance of the Ts65Dn mice, though the lack of observed effects of EGCG may be due to the relatively low numbers of Ts65Dn-EGCG treated mice that have completed testing so far. One notable trend is that we will continue to test additional mice to gain sufficient power to determine conclusively whether EGCG improves motor coordination performance in Ts65Dn mice.
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    Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice
    (Springer, 2020-06-26) Goodlett, Charles R.; Stringer, Megan; LaCombe, Jonathan; Patel, Roshni; Wallace, Joseph M.; Roper, Randall J.; Biology, School of Science
    Epigallocatechin-3-gallate (EGCG) is a candidate therapeutic for Down syndrome (DS) phenotypes based on in vitro inhibition of DYRK1A, a triplicated gene product of Trisomy 21 (Ts21). Consumption of green tea extracts containing EGCG improved some cognitive and behavioral outcomes in DS mouse models and in humans with Ts21. In contrast, treatment with pure EGCG in DS mouse models did not improve neurobehavioral phenotypes. This study tested the hypothesis that 200 mg/kg/day of pure EGCG, given via oral gavage, would improve neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model. Serum EGCG levels post-gavage were significantly higher in trisomic mice than in euploid mice. Daily EGCG gavage treatments over three weeks resulted in growth deficits in both euploid and trisomic mice. Compared to vehicle treatment, EGCG did not significantly improve behavioral performance of Ts65Dn mice in the multivariate concentric square field, balance beam, or Morris water maze tasks, but reduced swimming speed. Furthermore, EGCG resulted in reduced cortical bone structure and strength in Ts65Dn mice. These outcomes failed to support the therapeutic potential of EGCG, and the deleterious effects on growth and skeletal phenotypes underscore the need for caution in high-dose EGCG supplements as an intervention in DS.
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    Increased dosage and treatment time of Epigallocatechin-3-gallate (EGCG) negatively affects skeletal parameters in normal mice and Down syndrome mouse models
    (Public Library of Science, 2022-02-23) Jamal, Raza; LaCombe, Jonathan; Patel, Roshni; Blackwell, Matthew; Thomas, Jared R.; Sloan, Kourtney; Wallace, Joseph M.; Roper, Randall J.; Biology, School of Science
    Bone abnormalities affect all individuals with Down syndrome (DS) and are linked to abnormal expression of DYRK1A, a gene found in three copies in people with DS and Ts65Dn DS model mice. Previous work in Ts65Dn male mice demonstrated that both genetic normalization of Dyrk1a and treatment with ~9 mg/kg/day Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea and putative DYRK1A inhibitor, improved some skeletal deficits. Because EGCG treatment improved mostly trabecular skeletal deficits, we hypothesized that increasing EGCG treatment dosage and length of administration would positively affect both trabecular and cortical bone in Ts65Dn mice. Treatment of individuals with DS with green tea extract (GTE) containing EGCG also showed some weight loss in individuals with DS, and we hypothesized that weights would be affected in Ts65Dn mice after EGCG treatment. Treatment with ~20 mg/kg/day EGCG for seven weeks showed no improvements in male Ts65Dn trabecular bone and only limited improvements in cortical measures. Comparing skeletal analyses after ~20mg/kg/day EGCG treatment with previously published treatments with ~9, 50, and 200 mg/kg/day EGCG showed that increased dosage and treatment time increased cortical structural deficits leading to weaker appendicular bones in male mice. Weight was not affected by treatment in mice, except for those given a high dose of EGCG by oral gavage. These data indicate that high doses of EGCG, similar to those reported in some treatment studies of DS and other disorders, may impair long bone structure and strength. Skeletal phenotypes should be monitored when high doses of EGCG are administered therapeutically.