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Overexpression of\n                  <jats:italic>Dual-specificity tyrosine phosphorylation-regulated kinase-1A<\/jats:italic>\n                  (\n                  <jats:italic>DYRK1A<\/jats:italic>\n                  ), a gene on human chromosome 21 (Hsa21) and triplicated in individuals with Trisomy 21, contributes to neurodevelopmental delays associated with DS, and is a candidate for therapies to improve neurodevelopmental phenotypes. Male and female Ts65Dn DS model pups are trisomic for \u223c100 Hsa21 orthologs including\n                  <jats:italic>Dyrk1a,<\/jats:italic>\n                  and both sexes show significant DYRK1A overexpression on postnatal day 6 (P6) in the hippocampus, cerebral cortex, and cerebellum. This study tested the hypothesis that normalization of\n                  <jats:italic>Dyrk1a<\/jats:italic>\n                  copy number in Ts65Dn pups prior to P6 would diminish physical and behavioral developmental outcomes in Ts65Dn mice, thus providing a standard of comparison for success of interventions targeting\n                  <jats:italic>Dyrk1a.<\/jats:italic>\n                  At P3-P21, Ts65Dn compared to euploid pups showed sex-specific deficits in physical, motor, and behavioral development. Male Ts,\n                  <jats:italic>Dyrk1a<\/jats:italic>\n                  <jats:sup>+\/+\/Dox-Cre<\/jats:sup>\n                  mice showed improved emergence to running on P19, and both sexes of Ts,\n                  <jats:italic>Dyrk1a<\/jats:italic>\n                  <jats:sup>+\/+\/Dox-Cre<\/jats:sup>\n                  mice exhibited reduced isolation-induced ultrasonic vocalizations during the second postnatal week.\n                  <jats:italic>Dyrk1a<\/jats:italic>\n                  normalization in Ts65Dn pups did not improve all abnormal phenotypes, perhaps because of developmental dysregulation between\n                  <jats:italic>Dyrk1a<\/jats:italic>\n                  RNA and DYRK1A protein levels, involvement of other trisomic genes, or improvements in only adult mice.\n                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