Pharmacological strategies to combat the effect of Kcnj6 gene dose could be considered in an attempt to address changes in cognition in DS. Treatments to reduce the expression of Kcnj6 or modify the trafficking of Kir3.2 subunits might be considered, but at this time, to our knowledge, these approaches are not being explored. In contrast, inhibiting the activation of GABAB receptors appears feasible (Cramer et al., 2010; Kleschevnikov et al., 2012a), as are attempts to develop antagonists of Kir3.2 containing channels. In this study, we asked if acute suppression of Kir3.2 channel signaling could rescue synaptic plasticity. Like certain other serotonin re-uptake inhibitors, fluoxetine is an effective blocker of the Kir3.2 subunit-containing potassium channels (Kobayashi et al., 2003, 2004). At the concentration used in our experiments (10 μM), fluoxetine is estimated to have blocked about 50% of the current through the Kir3.2 potassium channels. Fluoxetine improved both STP and LTP in the DG of Ts65Dn mice. Since fluoxetine is an inhibitor of serotonin reuptake, it raises the question of whether the finding may be due to increased serotonin levels. However,
