SK2 channels are required for function and long-term survival of efferent synapses on mammalian outer hair cells

Cochlear hair cells use SK2 Currents to shape responses to cholinergic efferent feedback from the brain. Using SK2(-/-) mice, we demonstrate that, in addition to their previously defined role in modulating hair cell membrane potentials, SK2 channels are necessary for long-term survival of olivocochlear fibers and synapses. Loss of the SK2 gene also results a loss of electrically driven olivocochlear effects in vivo. and down regulation of ryanodine receptors involved in calcium-induced calcium release, the main inducer of nAChR evoked SK2 activity. Generation Of double-null mice lacking both the alpha 10 nAChR gene, loss of which results in hypertrophied olivocochlear terminals, and the SK2 gene, recapitulates the SK2(-/-) synaptic phenotype and gene expression, and also leads to clown regulation of alpha 9 nAChR gene expression. The data suggest a hierarchy of activity necessary to maintain early olivocochlear synapses at then, targets, with SK2 serving an epistatic, upstream, role to the nAChRs. (C) 2008 Elsevier Inc. All rights reserved