Down syndrome (DS), a genetic condition due to triplication of chromosome 21, is characterized by reduced proliferation of neural progenitor cells (NPCs) starting from early life stages. This defect is worsened by areduction of neuronogenesis (accompanied by an increase in astrogliogenesis)and dendritic spineatrophy. Since this triad of defects underliesintellectual disability, it seems importantto establish whether it is possible to pharmacologically correct these alterations. In this study, we exploited the Ts65Dn mouse model of DS in order to obtain an answer to this question. In the framework of an in vitrodrug-screening campaign of FDA/EMA-approved drugs,we found that the immunosuppressant cyclosporine A (CSA) restored proliferation, acquisitionof a neuronal phenotype,and maturation of neural progenitorcells (NPCs) from the subventricular zone (SVZ) of the lateral ventricle of Ts65Dn mice. Based on these findings, we treated Ts65Dn mice with CSA in the postnatal period P3-P15. We found that treatment fully restored NPC proliferation in the SVZ and in thesubgranular zone of the hippocampal dentate gyrus,and total number of hippocampal granule cells. Moreover, CSA enhanced development of dendritic spines on the dendritic arbor of the granule cells whose density even surpassed that of euploid mice.In hippocampal homogenates fromTs65Dn mice,we found that CSA normalizedthe excessive levels of p21, akey determinant of proliferation impairment.Results show that neonatal treatment with CSA restores the whole triad of defects of the trisomic brain. In DS CSA treatmentmay pose caveats because it is an immunosuppressant that may cause adverse effects. However, CSA analogues that mimic its effect without eliciting immunosuppressionmay represent practicable tools for ameliorating brain development in individuals with DS.

Neonatal treatment with cyclosporine A restores neurogenesis and spinogenesis in the Ts65Dn model of Down syndrome / Fiorenza Stagni, Maria Elisa Salvalai, Andrea Giacomini, Marco Emili, Beatrice Uguagliati, Er Xi, Mariagrazia Grilli, Renata Bartesaghi, Sandra Guidi. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - ELETTRONICO. - 129:(2019), pp. 44-55. [10.1016/j.nbd.2019.05.005]

Neonatal treatment with cyclosporine A restores neurogenesis and spinogenesis in the Ts65Dn model of Down syndrome

Fiorenza Stagni;Andrea Giacomini;Marco Emili;Beatrice Uguagliati;Renata Bartesaghi
;
Sandra Guidi
2019

Abstract

Down syndrome (DS), a genetic condition due to triplication of chromosome 21, is characterized by reduced proliferation of neural progenitor cells (NPCs) starting from early life stages. This defect is worsened by areduction of neuronogenesis (accompanied by an increase in astrogliogenesis)and dendritic spineatrophy. Since this triad of defects underliesintellectual disability, it seems importantto establish whether it is possible to pharmacologically correct these alterations. In this study, we exploited the Ts65Dn mouse model of DS in order to obtain an answer to this question. In the framework of an in vitrodrug-screening campaign of FDA/EMA-approved drugs,we found that the immunosuppressant cyclosporine A (CSA) restored proliferation, acquisitionof a neuronal phenotype,and maturation of neural progenitorcells (NPCs) from the subventricular zone (SVZ) of the lateral ventricle of Ts65Dn mice. Based on these findings, we treated Ts65Dn mice with CSA in the postnatal period P3-P15. We found that treatment fully restored NPC proliferation in the SVZ and in thesubgranular zone of the hippocampal dentate gyrus,and total number of hippocampal granule cells. Moreover, CSA enhanced development of dendritic spines on the dendritic arbor of the granule cells whose density even surpassed that of euploid mice.In hippocampal homogenates fromTs65Dn mice,we found that CSA normalizedthe excessive levels of p21, akey determinant of proliferation impairment.Results show that neonatal treatment with CSA restores the whole triad of defects of the trisomic brain. In DS CSA treatmentmay pose caveats because it is an immunosuppressant that may cause adverse effects. However, CSA analogues that mimic its effect without eliciting immunosuppressionmay represent practicable tools for ameliorating brain development in individuals with DS.
2019
Neonatal treatment with cyclosporine A restores neurogenesis and spinogenesis in the Ts65Dn model of Down syndrome / Fiorenza Stagni, Maria Elisa Salvalai, Andrea Giacomini, Marco Emili, Beatrice Uguagliati, Er Xi, Mariagrazia Grilli, Renata Bartesaghi, Sandra Guidi. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - ELETTRONICO. - 129:(2019), pp. 44-55. [10.1016/j.nbd.2019.05.005]
Fiorenza Stagni, Maria Elisa Salvalai, Andrea Giacomini, Marco Emili, Beatrice Uguagliati, Er Xi, Mariagrazia Grilli, Renata Bartesaghi, Sandra Guidi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/689168
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