Long-term depression in the hippocampus in vivo is associated with proteinphosphatase-dependent alterations in extracellular signal-regulated kinase

There is growing evidence that activation of either protein kinases or prot ein phosphatases determines the type of plasticity observed after different patterns of hippocampal stimulation. Because activation of the extracellul ar signal-regulated kinase (ERK) has been shown to be necessary for long-te rm potentiation, we investigated the regulation of ERK in long-term depress ion (LTD) in the adult hippocampus in vivo. We found that ERK immunoreactiv ity was decreased following the induction of LTD and that this decrease req uired NMDA receptor activation. The LTD-associated decrease in ERK immunore activity could be simulated in vitro via incubation of either purified ERK2 or hippocampal homogenates with either protein phosphatase 1 or protein ph osphatase 2A. The protein phosphatase-dependent decrease in ERK immunoreact ivity was inhibited by microcystin. Intrahippocampal administration of the protein phosphatase inhibitor okadaic acid blocked the LTD-associated decre ase in ERK2, but not ERK, immunoreactivity. Collectively, these data demons trate that protein phosphatases can decrease ERK immunoreactivity and that such a decrease occurs with ERK2 during LTD. These observations provide the first demonstration of a biochemical alteration of ERK in LTD.