Down syndrome (DS), trisomy 21, is caused by increased dose of genes present on 
human chromosome 21 (HSA21). The gene-dose hypothesis argues that a change in 
the dose of individual genes or regulatory sequences on HSA21 is necessary for 
creating DS-related phenotypes, including cognitive impairment. We focused on a 
possible role for Kcnj6, the gene encoding Kir3.2 (Girk2) subunits of a 
G-protein-coupled inwardly-rectifying potassium channel. This gene resides on a 
segment of mouse Chromosome 16 that is present in one extra copy in the genome 
of the Ts65Dn mouse, a well-studied genetic model of DS. Kir3.2 
subunit-containing potassium channels serve as effectors for a number of 
postsynaptic metabotropic receptors including GABAB receptors. Several studies 
raise the possibility that increased Kcnj6 dose contributes to synaptic and 
cognitive abnormalities in DS. To assess directly a role for Kcnj6 gene dose in 
cognitive deficits in DS, we produced Ts65Dn mice that harbor only 2 copies of 
Kcnj6 (Ts65Dn:Kcnj6++- mice). The reduction in Kcnj6 gene dose restored to 
normal the hippocampal level of Kir3.2. Long-term memory, examined in the novel 
object recognition test with the retention period of 24h, was improved to the 
level observed in the normosomic littermate control mice (2N:Kcnj6++). 
Significantly, both short-term and long-term potentiation (STP and LTP) was 
improved to control levels in the dentate gyrus (DG) of the Ts65Dn:Kcnj6++- 
mouse. In view of the ability of fluoxetine to suppress Kir3.2 channels, we 
asked if fluoxetine-treated DG slices of Ts65Dn:Kcnj6+++ mice would rescue 
synaptic plasticity. Fluoxetine increased STP and LTP to control levels. These 
results are evidence that increased Kcnj6 gene dose is necessary for synaptic 
and cognitive dysfunction in the Ts65Dn mouse model of DS. Strategies aimed at 
pharmacologically reducing channel function should be explored for enhancing 
cognition in DS.