Differential roles of Ca2+/calmodulin-dependent protein kinase II and mitogen-activated protein kinase activation in hippocampal long-term potentiation

The roles of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) an d mitogen-activated protein kinase (MAPK) in long-term potentiation (LTP) w ere investigated in the CA1 area of hippocampal slices, using electrophysio logical and biochemical approaches. A brief high-frequency stimulation, but not low-frequency stimulation, delivered to Schaffer collateral/commissura l afferents produced a stable LTP and activated both CaM kinase II and 42 k Da MAPK. Different from the activity of CaM kinase II, the increase in MAPK activity was transient. At a concentration of 50 mu M, but not of 30 mu M, PD098059, a potent inhibitor of MAPK kinase, markedly inhibited the induct ion of LTP. Although the two concentrations had similar inhibitory effects on MAPK activity, only 50 mM PD098059 suppressed the activation of CaM kina se II. Application of calmidazolium, an antagonist of calmodulin, blocked b oth CaM kinase II activation and the LTP induction without affecting the in crease in 42 kDa MAPK activity. Application of neurotrophin brain-derived n eurotrophic factor (BDNF) promoted the induction of LTP, with concomitant a ctivation of CaM kinase II. Under the same conditions, BDNF failed to activ ate MAPK in hippocampal slices. These results indicate that, although the L TP induction is accompanied by increases in two kinase activities, only CaM kinase II activation is required for this event.