A direct test of the impact of increased dose of specific genes is essential for defining contribution(s) to phenotypes. To address the impact of Kcnj6 triplication on cognitive phenotypes in DS, we genetically deleted the third copy by producing Ts65Dn mice with 2 copies of Kcnj6 (i.e., Ts65Dn:Kcnj6++−). Littermate Ts65Dn mice with three copies of Kcnj6 (Ts65Dn:Kcnj6+++) and normosomic mice (2N:Kcnj6++) served as controls. Reduction of the Kcnj6 gene dose restored to normal the level of Kir3.2, long term memory, and short- and long-term potentiation in the DG. Remarkably, pharmacologically inhibiting Kir3.2-containing channels also restored synaptic plasticity. The findings are evidence that increased expression of Kcnj6 is necessary for the significant cognitive impairment in this model of DS and suggests that strategies aimed at pharmacologically reducing channel function should be explored for enhancing cognition in DS.
