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  • Review Article
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Roles of serine/threonine phosphatases in hippocampel synaptic plasticity

Nature Reviews Neuroscience volume 2, pages 461–474 (2001)Cite this article

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 remodelling. The regulation of phosphatase activity can also have longer-lasting effects on synaptic function through the dephosphorylation of transcription factors, and so the control of gene expression.

Abstract

The regulation of glutamate-mediated excitatory neurotransmission has a critical role in many aspects of behaviour. Great effort has gone into understanding the signal transduction cascades and effectors recruited in these processes, and protein phosphorylation has been identified as an important element. Although initial research in the field focused on the activity-dependent activation of kinases and the kinase dependence of various forms of synaptic plasticity, it has become increasingly clear that phosphatases have an equally dynamic and critical role in the activity-dependent alterations of synaptic transmission. Here, we review the roles of serine/threonine phosphatases in synaptic plasticity.

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Figure 1: Isoform-specific subcellular distribution of phosphatases.
Figure 2: Postsynaptic-biased model of phosphatase localization and function.
Figure 3: Bi-directional regulation of CA1 LTP by genetic manipulation of PP2B activity.
Figure 4: Hypothetical model of the direction and time course of the regulation of phosphatase activity by LTP and LTD induction.

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Acknowledgements

We thank R. Colbran, C. Weitlauf and A. Vanhoose for critically reading the manuscript.

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Authors and Affiliations

  1. Department of Molecular Physiology and Biophysics, and Centre for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, 37232-0615, Tennessee, USA

    Danny G. Winder

  2. Division of Neuroscience, Baylor College of Medicine, Houston, 77030-3411, Texas, USA

    J. David Sweatt

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  1. Danny G. Winder
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DATABASE LINKS

PP1

PP2A

PP2B

CaMKII

I-1

DARPP-32

PKA

G-substrate

NR1

Yotiao

RII

NR2B

Spinophilin

Neurabin

D2 dopamine receptor

α2-Adrenergic receptor

p70 S6 kinase

NIPP-1

CK2

Calmodulin

FKBP12

CAIN

AKAP79

PSD-95

SAP97

iGluRs

CaMKIV

CREB

PKC

GluR1

NF-AT

mGluR5

AC9

ERK2

ERK/MAPK

MEK

MKPs

Glossary

OKADAIC ACID

A polyether fatty acid isolated from the dinoflagellate Prorocentrum lima and used as a potent inhibitor of protein phosphatases, especially types 1 and 2A.

CALYCULIN A

A metabolite of the Japanese marine sponge Discodermia calyx that has strong antitumour activity. It is a potent inhibitor of protein phosphatase types 1 and 2A.

MICROCYSTINS

Cyclic heptapeptide toxins produced by cyanobacteria. They are potent inhibitors of protein phosphatases 1 and 2A.

FK506

A member of the macrolide antibiotic family isolated from Streptomyces tsukubaensis. It binds to FK506-binding proteins (FKBPs) and serves as an immunosuppressant. In a complex with FKBPs, it can block the action of calcineurin.

CYCLOSPORIN A

A cyclic decapeptide isolated from the fungi Cylindrocarpon lucidum and Tolypocladium inflatum that serves as a potent immunosuppressive. When bound to cyclophilin, it can bind and inactivate calcineurin.

IMMUNOPHILIN

A generic term for proteins that can bind immunosuppressive drugs.

PDZ DOMAIN

peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. They can bind to the carboxyl termini of proteins, or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs-large, zona occludens-1).

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.

REVERSE TETRACYCLINE-DEPENDENT TRANSACTIVATOR SYSTEM

A system that allows the precise control of gene expression in eukaryotic systems through the administration of tetracycline or its analogues, for example, doxycycline. It is based on two key elements: a mutant form of the tetracycline-dependent transactivator protein (tTA) and the target gene under the control of a tTA-responsive element. Once these key elements have been transferred into eukaryotic cells, the mutant tTA is expressed, but does not bind the tTA-responsive element. Binding of the mutant tTA to the tTA-responsive element and initiation of transcription is then induced by the addition of tetracycline.

SILENT SYNAPSE

A synapse that contains NMDA receptors but no AMPA receptors and therefore is functionally silent during low-frequency, basal synaptic transmission.

CLATHRIN

A major structural component of coated vesicles that are implicated in protein transport. Clathrin heavy and light chains form a triskelion, the main building element of clathrin coats.

DYNAMIN

A small GTPase that is involved in endocytosis. It is thought to be involved in severing the connection between the nascent vesicle and the donor membrane.

MORRIS WATER MAZE

A learning task in which an animal is placed in a pool filled with opaque water and has to learn to escape to a hidden platform that is placed at a constant position. The animal must learn to use distal cues, and the spatial relationship between them and the position of the platform. Learning in this task involves the hippocampus.

BARNES MAZE

A learning task in which the animal is placed on a large, open table that has holes in the periphery. Only one of the holes has an escape tunnel, and the animal must learn to use distal cues to identify this hole and escape in the shortest possible time. Learning in this task involves the hippocampus.

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Winder, D., Sweatt, J. Roles of serine/threonine phosphatases in hippocampel synaptic plasticity. Nat Rev Neurosci 2, 461–474 (2001). https://doi.org/10.1038/35081514

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