title: Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3-gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome.
abstract: Cognitive disability is an unavoidable feature of Down syndrome (DS), a genetic disorder due to the triplication of human chromosome 21. DS is associated with alterations of neurogenesis, neuron maturation and connectivity that are already present at prenatal life stages. Recent evidence shows that pharmacotherapies can have a large impact on the trisomic brain provided that they are administered perinatally. Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, performs many actions in the brain, including inhibition of DYRK1A, a kinase that is over-expressed in the DS brain and contributes to the DS phenotype. Young adults with DS treated with EGCG exhibit some cognitive benefits, although these effects disappear with time. We deemed it extremely important, however, to establish whether treatment with EGCG at the initial stages of brain development leads to plastic changes that outlast treatment cessation. In the current study, we exploited the Ts65Dn mouse model of DS in order to establish whether pharmacotherapy with EGCG during peak of neurogenesis in the hippocampal dentate gyrus (DG) enduringly restores hippocampal development and memory performance. Euploid and Ts65Dn mice were treated with EGCG from postnatal day 3 (P3) to P15. The effects of treatment were examined at its cessation (at P15) or after one month (at P45). We found that at P15 treated trisomic pups exhibited restoration of neurogenesis, total hippocampal granule cell number and levels of pre- and postsynaptic proteins in the DG, hippocampus and neocortex. However, at P45 none of these effects were still present, nor did treated Ts65Dn mice exhibit any improvement in hippocampus-dependent tasks. These findings show that treatment with EGCG carried out in the neonatal period rescues numerous trisomy-linked brain alterations. However, even during this, the most critical time window for hippocampal development, EGCG does not elicit enduring effects on the hippocampal physiology.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Fiorenza
authors.initials: F
authors.lastname: Stagni
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Giacomini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Emili
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Trazzi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Guidi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Sassi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Ciani
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rimondini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. Electronic address: renata.bartesaghi@unibo.it.
authors.forename: Renata
authors.initials: R
authors.lastname: Bartesaghi
mesh_terms: D000818:Animals; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D013997:Time Factors
chemical_list: D018696:Neuroprotective Agents; D002392:Catechin; C045651:epigallocatechin gallate
keywords: Down syndrome; EGCG; brain development; early pharmacotherapy; hippocampal dentate gyrus; memory