Phosphorylation of K(+) channels at single residues regulates memory formation

Phosphorylation is a ubiquitous post-translational modification of proteins, and a known physiological regulator of K(+) channel function. Phosphorylation of K(+) channels by kinases has long been presumed to regulate neuronal processing and behavior. Although circumstantial evidence has accumulated from behavioral studies of vertebrates and invertebrates, the contribution to memory of single phosphorylation sites on K(+) channels has never been reported. We have used gene targeting in mice to inactivate protein kinase A substrate residues in the fast-inactivating subunit K(v)4.2 (T38A mutants), and in the small-conductance Ca(2+)-activated subunit SK1 (S105A mutants). Both manipulations perturbed a specific form of memory, leaving others intact. T38A mutants had enhanced spatial memory for at least 4 wk after training, whereas performance in three tests of fear memory was unaffected. S105A mutants were impaired in passive avoidance memory, sparing fear, and spatial memory. Together with recent findings that excitability governs the participation of neurons in a memory circuit, this result suggests that the memory type supported by neurons may depend critically on the phosphorylation of specific K(+) channels at single residues.