Activation of protein kinase A contributes to the expression but not the induction of long-term hyperexcitability caused by axotomy of Aplysia sensory neurons

Nociceptive sensory neurons (SNs) in Aplysia provide useful models to study both memory and adaptive responses to nerve injury. Induction of long-term memory in many species, including Aplysia, is thought to depend on activat ion of cAMP-dependent protein kinase (PKA). Because Aplysia SNs display sim ilar alterations in models of memory and after nerve injury, a plausible hy pothesis is that axotomy triggers memory-like modifications by activating P KA in damaged axons. The present study disproves this hypothesis. SN axotom y was produced by (1) dissociation of somata from the ganglion [which is sh own to induce long-term hyperexcitability (LTH)], (2) transection of neurit es of dissociated SNs growing in vitro, or (3) peripheral nerve crush. Appl ication of the competitive PKA inhibitor Rp-8-CPT-cAMPS at the time of axot omy failed to alter the induction of LTH by each form of axotomy, although the inhibitor antagonized hyperexcitability produced by 5-HT application. S trong activation of PKA in the nerve by coapplication of a membrane-permean t analog of cAMP and a phosphodiesterase inhibitor was not sufficient to in duce LTH of either the SN somata or axons. Furthermore, nerve crush failed to activate axonal PKA or stimulate its retrograde transport. Therefore, PK A activation plays little if any role in the induction of LTH by axotomy. H owever, the expression of LTH was reduced by intracellular injection of the highly specific PKA inhibitor PKI several days after nerve crush. This sug gests that long-lasting activation of PKA in or near the soma contributes t o the maintenance of long-term modifications produced by nerve injury.