An understanding of the genetic and molecular bases for developmental delay in Down syndrome (DS) will be critical for the design of strategies to improve cognitive function in DS; however, a fundamental gap exists in our knowledge of the effects of trisomy on juvenile cortical development when activity sculpts the functional circuitry of the brain. The mouse visual system affords a novel window into this process with robust, activity-dependent behaviors that can be elicited in a well-characterized, neural circuit. Ts65Dn mice, a well-studied model of DS, demonstrate a defect in ocular dominance plasticity (ODP), a juvenile visual cortical response to loss of input from one eye that in normal mice results in strengthening of cortical responses to stimulation of the nondeprived eye. Ts1Rhr mice harbor a smaller duplication and demonstrate similar plasticity impairment. Within the Ts1Rhr duplication, preliminary data indicate that the gene encoding Dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1A) drives impairment when trisomic and this impairment can be rescued by restoration of Dyrk1a disomy. Dyrk1a haploinsufficiency also impairs ODP, suggesting that too little DYRK1A activity can be as deleterious as too much activity; identifying DYRK1A effectors may provide additional, potentially safer, drug targets as well as reveal the underlying mechanism of DYRK1A-driven impairment. In vitro studies have impli- cated DYRK1A in hippocampal plasticity impairment and in behavioral phenotypes, though the mechanisms underlying these phenotypes are not well understood. The central hypothesis is that Dyrk1a trisomy causes aberrant kinase activity that disrupts neuronal function and consequently impairs cortical circuit function during juvenile development in DS. The experiments of Aim 1 explore the extent to which Dyrk1a trisomy can account for impairment in the context of model mice with a larger complement of trisomic genes (Dp1Yey mice; Aim 1a), and whether postnatal, pharmacologic inhibition of DYRK1A can restore ODP in Ts1Rhr mice (Aim 1b) using awake optical imaging of intrinsic signals and immediate early gene expression to measure cortical responses to visual stimulation. Aim 2 focuses on the cellular and molecular bases for circuit impairment in Dyrk1a trisomic mice. The Cre-Lox recombination system will be used to assess whether Dyrk1a trisomy is required in excitatory or in inhibitory neurons to impair ODP in Ts1Rhr mice (Aim 2a). The cellular and physiologic effects of Dyrk1a trisomy will be assessed through patch clamp electrophysiologic analysis of L4 principal neurons, the primary cortical neurons that receive input from both eyes (Aim 2b). To identify DYRK1A effectors, laser capture micros- copy will be coupled with mass spectrometry to perform phosphoproteomic analysis of visual cortical layer 4 in Ts1Rhr mice with 2 or with 3 copies of Dyrk1A in the presence or absence of a challenge of loss of vision in one eye (Aim 2c)....