Is persistent activity of calcium/calmodulin-dependent kinase required forthe maintenance of LTP?

Calcium/calmodulin-dependent protein kinase II (CaMKII) is concentrated in the postsynaptic density (PSD) and plays an important role in the induction of long-term potentiation (LTP). Because this kinase is persistently activ ated after the induction, its activity could also be important for LTP main tenance. Experimental tests of this hypothesis, however, have given conflic ting results. In this paper we further explore the role of postsynaptic CaM KII in induction and maintenance of LTP. Postsynaptic application of a CaMK II inhibitor [autocamtide-3 derived peptide inhibitor (AC3-I), 2 mM] blocke d LTP induction but had no detectable affect on N-methyl-D-aspartate (NMDA) -mediated synaptic transmission, indicating that the primary function of Ca MKII in LTP is downstream from NMDA channel function. We next explored vari ous methodological factors that could account for conflicting results on th e effect of CaMKII inhibitors on LTP maintenance. In contrast to our previo us work, we now carried out experiments at higher temperature (33 degreesC) , used slices from adult animals, and induced LTP using a tetanic stimulati on. However, we still found that LTP maintenance was not affected by postsy naptic application of AC3-I. Furthermore the inhibitor did not block LTP ma intenance under conditions designed to enhance the Ca2+-dependent activity of protein phosphatases 1 and 2B (elevated Ca2+, calmodulin, and an inhibit or of protein kinase A). We also tested the possibility that CaMKII inhibit or might not be able to affect CaMKII once it was inserted into the PSD. In whole-brain extracts, AC3-I blocked autophosphorylation of both soluble an d particulate/PSD CaMKII with similar potencies although the potency of the inhibitor toward other CaMKII substrates varied. Thus we were unable to de monstrate a functional role of persistent Ca2+-independent CaMKII activity in LTP maintenance. Possible explanations of the data are discussed.