Hippocampus-dependent long-term memory is impaired both in DS (Carlesimo et al., 1997; Vicari et al., 2000) and in mouse genetic models of DS (Escorihuela et al., 1998). In agreement with earlier findings (Fernandez et al., 2007; Kleschevnikov et al., 2012a), novel object recognition memory with the retention period of 24 h was significantly impaired in Ts65Dn mice containing 3 copies of Kcnj6. Remarkably, removal of an extra copy of Kcnj6 restored both synaptic plasticity and long-term memory to the levels observed in 2N controls. This data points to increased expression of Kir3.2 as suppressing hippocampal synaptic plasticity and resulting in cognitive impairment. Complementing our findings documented herein for a necessary role played by Kcnj6 dose in synaptic plasticity and cognition are studies in which the presence of 4–5 extra copies of Kcnj6 in the genome of normal mice led to reduced synaptic plasticity and cognitive impairment reminiscent of DS (Cooper et al., 2012). Thus, the evidence points to increased Kcnj6 dose as necessary and possibly sufficient for deficits in synaptic plasticity in some tests of cognition in models of DS.
