Preclinical Treatment of Neurobehavioral and Brain Structural Deficits in the Ts65Dn Down Syndrome Mouse Model with a Novel Dyrk1a Inhibitor

Down syndrome (DS) is a disorder caused by triplication of human chromosome 21 (Hsa21), and is characterized by multiple cognitive deficits and structural deficiencies in the hippocampus, cerebral cortex, and cerebellum. One of the genes triplicated in individuals with DS, Dual-specificity tyrosine phosphorylation-regulated kinase 1a (Dyrk1a), is overexpressed at certain developmental timepoints, and has been linked to learning and memory deficits in DS. The trisomic Ts65Dn mouse model of DS carries three copies of approximately half of the genes triplicated in human DS including Dyrk1a and exhibits many of the behavioral, cognitive, proliferative, and craniofacial abnormalities seen in humans with DS. Inhibition of Dyrk1a has been proposed as a means to improve DS cognitive deficits, and compounds currently in clinical trials as anticancer agents include Dyrk1a inhibitors. This study tested the hypothesis that treatment with a novel Dyrk1a inhibitor in the DS mouse model will improve behavioral development and rescue hippocampal neurogenesis in preweaning Ts65Dn mice compared to euploid littermates. This study utilized open field activity and a homing task to assess behavioral consequences of the treatment. Bromodeoxyuridine (BrdU) was then injected, brains harvested two hours later, and immunohistochemistry of BrdU-labeled cells was used to quantify proliferation of neuroprogenitor cells (NPC) in the subgranular zone of the hippocampal dentate gyrus. It is hypothesized that selective inhibition of Dyrk1a will improve deficits on the neurobehavioral tasks and restore proliferation of the NPCs in Ts65Dn mice to levels of euploid controls. If confirmed, the study would provide evidence that targeting trisomic Dyrk1a with inhibitors during age-specific periods of overexpression is a viable pharmacotherapy for Down syndrome