Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome

Torres, M.D. Martínez del Valle; García, Otto L.; Tang, Cindy; Busciglio, Jorge

doi:10.1016/j.freeradbiomed.2017.09.025

Cited by 35 publications

(28 citation statements)

References 71 publications

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“…Developmental defects in the dentate gyrus, altered dendritic spine morphology and reduced spine and synaptic density have also been observed (Guidi et al, 2018). These last features have been associated with the astrocyte-secreted thrombospondin 1 (Torres et al, 2018). Recent studies also demonstrated an important role of PGC-1α and of its targets in the formation and maintenance of hippocampal dendritic spines and synapses (Cheng et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells

et al. 2019

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Mitochondrial dysfunction plays a primary role in neurodevelopmental anomalies and neurodegeneration of Down syndrome (DS) subjects. For this reason, targeting mitochondrial key genes, such as PGC-1α/PPARGC1A , is emerging as a good therapeutic approach to attenuate cognitive disability in DS. After demonstrating the efficacy of the biguanide metformin (a PGC-1α activator) in a cell model of DS, we extended the study to other molecules that regulate the PGC-1α pathway acting on PPAR genes. We, therefore, treated trisomic fetal fibroblasts with different doses of pioglitazone (PGZ) and evaluated the effects on mitochondrial dynamics and function. Treatment with PGZ significantly increased mRNA and protein levels of PGC-1α. Mitochondrial network was fully restored by PGZ administration affecting the fission-fusion mitochondrial machinery. Specifically, optic atrophy 1 ( OPA1 ) and mitofusin 1 ( MFN1 ) were upregulated while dynamin-related protein 1 ( DRP1 ) was downregulated. These effects, together with a significant increase of basal ATP content and oxygen consumption rate, and a significant decrease of reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in trisomic cells. In conclusion, we demonstrate that PGZ is able to improve mitochondrial phenotype even at low concentrations (0.5 μM). We also speculate that a combination of drugs that target mitochondrial function might be advantageous, offering potentially higher efficacy and lower individual drug dosage.

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Section: Discussionmentioning

confidence: 99%

Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells

et al. 2019

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“…Among the genes located on HSA21 there are several genes that encode receptors for interferons (IFN) (Ferrando‐Miguel et al, 2003). Recent evidence shows that thrombospondin‐1, a protein secreted by astrocytes which is fundamental for spinogenesis, is reduced in the Ts65Dn mouse and DS brains and that this defect is due to upregulation of IFN‐γ signaling (Torres, Garcia, Tang, & Busciglio, 2018). In addition to triplication of Chromosome 21 genes, individuals with DS exhibit overexpression of Chromosome 21 miR‐155, miR‐802, miR‐125b‐2, let‐7c, and miR‐99a (Siew, Tan, Babaei, Cheah, & Ling, 2013).…”

Section: Discussionmentioning

confidence: 99%

Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in theTs65Dnmodel of Down syndrome

et al. 2021

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Down syndrome (DS), a genetic condition caused by triplication of chromosome 21, is characterized by alterations in various cognitive domains, including hippocampus‐dependent memory functions, starting from early life stages. The major causes of intellectual disability in DS are prenatal neurogenesis alterations followed by impairment of dendritic development in early infancy. While there is evidence that the Ts65Dn mouse, the most widely used model of DS, exhibits dendritic alterations in adulthood, no studies are available regarding the onset of dendritic pathology. The goal of the current study was to establish whether this model exhibits early dendritic alterations in the hippocampus, a region whose function is severely damaged in DS. To this purpose, in Golgi‐stained brains, we evaluated the dendritic arborization and dendritic spines of the granule cells of the hippocampal dentate gyrus in Ts65Dn mice aged 8 (P8) and 15 (P15) days. While P15 Ts65Dn mice exhibited a notably hypotrophic dendritic arbor and a reduced spine density, P8 mice exhibited a moderate reduction in the number of dendritic ramifications and no differences in spine density in comparison with their euploid counterparts. Both in P8 and P15 mice, spines were longer and had a longer neck, suggesting possible alterations in synaptic function. Moreover, P8 and P15 Ts65Dn mice had more thin spines and fewer stubby spines in comparison with euploid mice. Our study provides novel evidence on the onset of dendritic pathology, one of the causes of intellectual disability in DS, showing that it is already detectable in the dentate gyrus of Ts65Dn pups. This evidence strengthens the suitability of this model of DS as a tool to study dendritic pathology in DS and to test the efficacy of early therapeutic interventions aimed at ameliorating hippocampal development and, therefore, memory functions in children with DS.

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“…Imaging studies in children and adults with these disorders have revealed altered functional connectivity in brain activation patterns, unusual density of white matter tracts, altered cortical thickness, microencephaly and macroencephaly, depending on the genetic mutation 104–108 . Unusual patterns of neuronal dendritic spine morphology have been reported in human postmortem analyses 109–112 . A large number of studies detected analogous abnormalities in dendritic spine morphology in mutant mouse models of neurodevelopmental disorders with intellectual disabilities 43,50,78,111,113–120 .…”

Section: Discussionmentioning

confidence: 99%

Spaced training improves learning in Ts65Dn and Ube3a mouse models of intellectual disabilities

Lauterborn

Schultz

et al. 2019

Transl Psychiatry

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Benefits of distributed learning strategies have been extensively described in the human literature, but minimally investigated in intellectual disability syndromes. We tested the hypothesis that training trials spaced apart in time could improve learning in two distinct genetic mouse models of neurodevelopmental disorders characterized by intellectual impairments. As compared to training with massed trials, spaced training significantly improved learning in both the Ts65Dn trisomy mouse model of Down syndrome and the maternally inherited Ube3a mutant mouse model of Angelman syndrome. Spacing the training trials at 1 h intervals accelerated acquisition of three cognitive tasks by Ts65Dn mice: (1) object location memory, (2) novel object recognition, (3) water maze spatial learning. Further, (4) spaced training improved water maze spatial learning by Ube3a mice. In contrast, (5) cerebellar-mediated rotarod motor learning was not improved by spaced training. Corroborations in three assays, conducted in two model systems, replicated within and across two laboratories, confirm the strength of the findings. Our results indicate strong translational relevance of a behavioral intervention strategy for improving the standard of care in treating the learning difficulties that are characteristic and clinically intractable features of many neurodevelopmental disorders.

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Dendritic spine pathology and thrombospondin-1 deficits in Down syndrome

Cited by 35 publications

References 71 publications

Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells

Pioglitazone Improves Mitochondrial Organization and Bioenergetics in Down Syndrome Cells

Early appearance of developmental alterations in the dendritic tree of the hippocampal granule cells in theTs65Dnmodel of Down syndrome

Spaced training improves learning in Ts65Dn and Ube3a mouse models of intellectual disabilities

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