Protein kinase C-dependent modulation of Na+ currents increases the excitability of rat neocortical pyramidal neurones

1. The effect of the protein kinase C (PKC) activator 1-oleoyl-2-acetyl-sn- glycerol (OAG) on TTS-sensitive Na+ currents in neocortical pyramidal neuro nes was evaluated using voltage-clamp and intracellular current-clamp recor dings. 2. In pyramid-shaped dissociated neurones, the addition of OAG to the super fusing medium consistently led to a 30% reduction in the maximal peak ampli tude of the transient sodium current (I-Na,I-T) evoked from a holding poten tial of -70 mV. We attributed this inhibitory effect to a significant negat ive shift of the voltage dependence of steady-state channel inactivation (o f approximately 14 mV). The inhibitory effect was completely prevented by h yperpolarising prepulses to potentials that were more negative than -80 mV. A small but significant leftward shift of I-Na,I-P activation was also obs erved, resulting in a slight increase of the currents evoked by test pulses at potentials: more negative then -35 mV. 3. In the presence of GAG, the activation of the persistent fraction of the Na+ current (I-Na,I-P) evoked by means of slow ramp depolarisations was co nsistently shifted in the negative direction by 3.9 +/- 0.5 mV, while the p eak amplitude of the current was unaffected. 4. In slice experiments, the OAG perfusion enhanced a subthreshold depolari sing rectification affecting the membrane response to the injection of posi tive current pulses, and thus led the neurones to fire in response to signi ficantly low er depolarising stimuli than those needed under control condit ions. This effect was attributed to an GAG-induced enhancement of I-Na,I-P since it was observed in the same range of potentials over which I-Na,I-P a ctivates and was completely abolished by TTX. 5. The qualitative firing characteristics of both the intrinsically burstin g and regular spiking neurones were unaffected when OAG was added to the ph ysiological perfusing medium, but their firing frequency increased in respo nse to slight suprathreshold depolarisations. 6. The obtained results suggest that physiopathological events working thro ugh PKC activation can increase neuronal excitability by directly amplifyin g the I-Na,I-P-dependent subthroshold depolarisation, and that this facilit ating effect may override the expected reduction in nearonal excitability d eriving from OAG-induced inhibition of the maximal I-Na,I-P peak amplitude.