Distinct roles of CaMKII and PKA in regulation of firing patterns and K+ currents in Drosophila neurons

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the cAMP-depen dent protein kinase A (PKA) cascades have been implicated in neural mechani sms underlying learning and memory as supported by mutational analyses of t he two enzymes in Drosophila. While there is mounting evidence for their ro les in synaptic plasticity, less attention has been directed toward their r egulation of neuronal membrane excitability and spike information coding. H ere we report genetic and pharmacological analyses of the roles of PKA and CaMKII in the firing patterns and underlying K+ currents in cultured Drosop hila central neurons. Genetic perturbation of the catalytic subunit of PKA (DC0) did not alter the action potential duration but disrupted the frequen cy coding of spike-train responses to constant current injection in a subpo pulation of neurons. In contrast, selective inhibition of CaMKII by the exp ression of an inhibitory peptide in ala transformants prolonged the spike d uration but did not affect the spike frequency coding. Enhanced membrane ex citability, indicated by spontaneous bursts of spikes, was observed in CaMK II-inhibited but not in PKA-diminished neurons. In wild-type neurons, the s pike train firing patterns were highly reproducible under consistent stimul us conditions. However, disruption of either of these kinase pathways led t o variable firing patterns in response to identical current stimuli deliver ed at a low frequency. Such variability in spike duration and frequency cod ing may impose problems for precision in signal processing in these protein kinase learning mutants. Pharmacological analyses of mutations that affect specific K+ channel subunits demonstrated distinct effects of PKA and CaMK II in modulation of the kinetics and amplitude of different K+ currents. Th e results suggest that PKA modulates Shaker A-type currents, whereas CaMKII modulates Shal-A type currents plus delayed rectifier Shab currents. Thus differential regulation of K+ channels may influence the signal handling ca pability of neurons. This study provides support for the notion that, in ad dition to synaptic mechanisms, modulations in spike activity patterns may r epresent an important mechanism for learning and memory that should be expl ored more fully.