Browsing by Subject "Learning and memory"

Now showing 1 - 3 of 3
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    Cdk5 activity in the brain - multiple paths of regulation
    (The Company of Biologists, 2014-06-01) Shah, Kavita; Lahiri, Debomoy; Department of Medical and Molecular Genetics, IU School of Medicine
    Cyclin dependent kinase-5 (Cdk5), a family member of the cyclin-dependent kinases, plays a pivotal role in the central nervous system. During embryogenesis, Cdk5 is indispensable for brain development and, in the adult brain, it is essential for numerous neuronal processes, including higher cognitive functions such as learning and memory formation. However, Cdk5 activity becomes deregulated in several neurological disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, which leads to neurotoxicity. Therefore, precise control over Cdk5 activity is essential for its physiological functions. This Commentary covers the various mechanisms of Cdk5 regulation, including several recently identified protein activators and inhibitors of Cdk5 that control its activity in normal and diseased brains. We also discuss the autoregulatory activity of Cdk5 and its regulation at the transcriptional, post-transcriptional and post-translational levels. We finally highlight physiological and pathological roles of Cdk5 in the brain. Specific modulation of these protein regulators is expected to provide alternative strategies for the development of effective therapeutic interventions that are triggered by deregulation of Cdk5. © 2014. Published by The Company of Biologists Ltd.
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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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    Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome
    (Springer Nature, 2024-12-05) Eom, Tae-Yeon; Schmitt, J. Eric; Li, Yiran; Davenport, Christopher M.; Steinberg, Jeffrey; Bonnan, Audrey; Alam, Shahinur; Ryu, Young Sang; Paul, Leena; Hansen, Baranda S.; Khairy, Khaled; Pelletier, Stephane; Pruett-Miller, Shondra M.; Roalf, David R.; Gur, Raquel E.; Emanuel, Beverly S.; McDonald-McGinn, Donna M.; Smith, Jesse N.; Li, Cai; Christie, Jason M.; Northcott, Paul A.; Zakharenko, Stanislav S.; Medical and Molecular Genetics, School of Medicine
    Neurodevelopmental disorders are thought to arise from intrinsic brain abnormalities. Alternatively, they may arise from disrupted crosstalk among tissues. Here we show the local reduction of two vestibulo-cerebellar lobules, the paraflocculus and flocculus, in mouse models and humans with 22q11.2 deletion syndrome (22q11DS). In mice, this paraflocculus/flocculus dysplasia is associated with haploinsufficiency of the Tbx1 gene. Tbx1 haploinsufficiency also leads to impaired cerebellar synaptic plasticity and motor learning. However, neural cell compositions and neurogenesis are not altered in the dysplastic paraflocculus/flocculus. Interestingly, 22q11DS and Tbx1+/- mice have malformations of the subarcuate fossa, a part of the petrous temporal bone, which encapsulates the paraflocculus/flocculus. Single-nuclei RNA sequencing reveals that Tbx1 haploinsufficiency leads to precocious differentiation of chondrocytes to osteoblasts in the petrous temporal bone autonomous to paraflocculus/flocculus cell populations. These findings suggest a previously unrecognized pathogenic structure/function relation in 22q11DS in which local skeletal deformity and cerebellar dysplasia result in behavioral deficiencies.