Kcnj6 expression is increased in mouse models of DS (Laffaire et al., 2009). Encoded by Kcnj6, the Kir3.2 subunit of inwardly rectifying potassium channels is widely expressed in brain regions important for cognition, including neocortex and hippocampus (Murer et al., 1997). Kir3.2 forms functional potassium channels as heterotetramers in combination with Kir3.1 and other subunits (Liao et al., 1996; Wischmeyer et al., 1997). The Kir3.2 subunit-containing potassium channels serve as effectors for a number of postsynaptic receptors, including GABAergic GABAB, serotoninergic 5HT-1A, cholinergic m2, and adrenergic A1 (Mark and Herlitze, 2000; Yamada et al., 1998). GABAB receptors mediate ‘slow’ type IPSCs via activation of Kir3.2 channels (Nicoll, 2004). Steady-state activation of Kir3.2-containing potassium channels also contributes to neuronal hyperpolarization (Luscher et al., 1997). Since potassium channels critically control neuronal hyperpolarization, abnormalities in Kir3.2 subunits are readily envisioned as significantly impacting brain functions. Consistent with this view, a missense mutation of Kcnj6 altering the pore-forming domain of the potassium channel is responsible for the ‘weaver’ phenotype, characterized by abnormal development of the cerebellum (Patil et al., 1995). In addition, a heterozygous
