title: Chronic P7C3 treatment restores hippocampal neurogenesis in the Ts65Dn mouse model of Down Syndrome [Corrected].
abstract: Down syndrome (DS) is the most common genetic cause of intellectual disability and developmental delay. In addition to cognitive dysfunction, DS patients are marked by diminished neurogenesis, a neuropathological feature also found in the Ts65Dn mouse model of DS. Interestingly, manipulations that enhance neurogenesis - like environmental enrichment or pharmacological agents - improve cognition in Ts65Dn mice. P7C3 is a proneurogenic compound that enhances hippocampal neurogenesis, cell survival, and promotes cognition in aged animals. However, this compound has not been tested in the Ts65Dn mouse model of DS. We hypothesized that P7C3 treatment would reverse or ameliorate the neurogenic deficits in Ts65Dn mice. To test this, adult Ts65Dn and age-matched wild-type (WT) mice were administered vehicle or P7C3 twice daily for 3 months. After 3 months, brains were examined for indices of neurogenesis, including quantification of Ki67, DCX, activated caspase-3 (AC3), and surviving BrdU-immunoreactive(+) cells in the granule cell layer (GCL) of the hippocampal dentate gyrus. P7C3 had no effect on total Ki67+, DCX+, AC3+, or surviving BrdU+ cells in WT mice relative to vehicle. GCL volume was also not changed. In keeping with our hypothesis, however, P7C3-treated Ts65Dn mice had a significant increase in total Ki67+, DCX+, and surviving BrdU+ cells relative to vehicle. P7C3 treatment also decreased AC3+ cell number but had no effect on total GCL volume in Ts65Dn mice. Our findings show 3 months of P7C3 is sufficient to restore the neurogenic deficits observed in the Ts65Dn mouse model of DS.
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390,USA.
authors: Sarah E
authors: SE
authors: Latchney
authors: Department of Neurology & Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8813, USA.
authors: Thomas C
authors: TC
authors: Jaramillo
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390,USA.
authors: Phillip D
authors: PD
authors: Rivera
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390,USA. Electronic address: amelia.eisch@utsouthwestern.edu.
authors: Amelia J
authors: AJ
authors: Eisch
authors: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390,USA; Department of Neurology & Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390-8813, USA. Electronic address: craig.powell@utsouthwestern.edu.
authors: Craig M
authors: CM
authors: Powell
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000089662:Doublecortin Protein; D004314:Down Syndrome / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D055495:Neurogenesis; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002227:Carbazoles; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018696:Neuroprotective Agents; C552520:P7C3 compound
keywords: AC3; BrdU; Dentate gyrus; Doublecortin; Ki67; Neuronal survival