Roles of serine/threonine phosphatases in hippocampel synaptic plasticity

Key Points Protein phosphatases have long been regarded as working in the background while kinases assume the important role of protein phosphorylation. This view has gradually changed with the realization that phosphatases are actively involved in the control of many cellular processes. In the nervous system, the involvement of protein phosphatases in synaptic plasticity has been extensively studied and constitutes the central topic of this article. The three best characterized serine/threonine phosphatases in brain are protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and calcineurin (PP2B). Each of these is present in the hippocampus, although their precise patterns of expression show some variation. The activity of protein phosphatases is tightly regulated. Several regulatory mechanisms have been described, and they include the phosphorylation of regulatory subunits, the direct regulation of phosphatase activity by calcium, and their regulation by alterations in the subcellular localization of phosphatase and/or substrate. Neurons have taken advantage of this diversity by using phosphatases to trigger and maintain long-lasting changes in synaptic efficacy. A cAMP-dependent protein kinase (PKA)-dependent suppression of PP1 activity seems to participate in the induction of long-term potentiation (LTP). This suppression depends on the phosphorylation of an endogenous phosphatase inhibitor. Similarly, PP2B appears to constrain LTP induction in CA1, as indicated by extensive pharmacological and genetic evidence. Moreover, a persistent downregulation of PP2A activity might be involved in the maintenance of LTP. There is abundant pharmacological, genetic and biochemical evidence for the involvement of PP1/PP2A and/or PP2B activation in the induction of long-term depression (LTD). In addition, phosphatases are also involved in depotentiation — the reversal of LTP. However, the mechanisms involved in depotentiation might not necessarily be the same as those used during LTD induction; in the former, phosphatases might have to dephosphorylate specific substrates originally affected by LTP induction. α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits have been identified as prime targets of phosphatase action in neurons. So, dephosphorylation of AMPA receptors can modulate channel properties and their availability on the cell membrane. Similarly, phosphatases can regulate cytoskeletal elements and therefore affect synaptic remo