Phorbol esters that activate protein kinase C induce long-term changes of membrane excitability and postsynaptic...

Intracellularly injected tumor promoter phorbol esters (PhEs) that activate protein kinase C (PKC) increased the excitability and altered the postsynaptic responses of neurons of the motor cortex of awake cats. PhEs increased the amplitude and duration of EPSPs and decreased the amplitude and durations of IPSPs. No consistent changes in resting membrane parameters that would account for these modifications were found. Corresponding changes in peak excitatory and inhibitory postsynaptic currents (EPSCs, IPSCs) were measured directly with the single electrode voltage clamp technique. The changes lasted for 50 min or longer. Quantitative analysis of EPSCs in response to ventrolateral thalamic stimulation and IPSCs in response to pyramidal tract stimulation made in a subgroup of fast PT cells suggested that PhE acted within the injected neuron rather than presynaptically to alter the synaptic currents. PhE also reduced a voltage-dependent, 3-aminopyridine sensitive fast outward current (IA) and an apamin and EGTA sensitive slow outward current (IK(Ca]. Control injections of a phorbol ester that did not activate PKC failed to induce changes in synaptic responses or resting membrane properties. These observations provide the first evidence that activation of PKC, in vivo, can induce long-lasting changes in synaptic responses of neocortical neurons by direct modification of postsynaptic ion channel conductivities.