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MAPK cascade signalling and synaptic plasticity

Key Points

  • In mature neurons, the mitogen-activated protein kinase (MAPK) cascade that leads to the activation of extracellular signal-regulated kinases (ERKs) is stimulated by excitatory glutamatergic signalling, and might therefore have a role in synaptic plasticity.

  • Elucidation of the roles of ERKs in the brain has been aided by the development of specific inhibitors of MAPK cascades. Inhibitors have been used to block the induction of long-term potentiation in the hippocampus. ERK-dependency has since been demonstrated for many other forms of synaptic plasticity.

  • Experiments that used inhibitors in behaving animals have indicated that ERK is involved in learning and memory (spatial learning, fear conditioning and conditioned taste aversion).

  • At the cellular level, ERK activity influences two processes that probably underlie changes in synaptic transmission — the activity of postsynaptic AMPA receptors, and structural plasticity.

  • Active ERK is present in the nuclei of stimulated cells, as well as in the cytoplasm and dendrites, indicating that the ERK cascade controls phosphorylation of targets both within nuclei and close to synapses.

  • Substrates for the ERK cascade during synaptic plasticity probably include the voltage-dependent potassium channel KV4.2, cytoskeletal proteins and transcription factors such as Elk1 and CREB.

  • p38 MAPK is highly expressed in the adult brain. Evidence is emerging that the kinase cascade leading to the activation of this MAPK is also a key regulator of synaptic plasticity.

Abstract

The mitogen-activated protein kinase (MAPK) cascade that leads to the activation of extracellular signal-regulated kinases-1 and -2 (ERK1 and ERK2) has a key role in the differentiation of some cell types and the proliferation of others. However, several recent reports implicate this cascade in the control of synaptic plasticity in the adult brain. ERK signalling seems to be essential for characterized neuronal transcriptional events, and might also regulate synaptic targets to control plasticity. Another recently emerging story is the involvement of a 'parallel' but distinct kinase cascade leading to the activation of p38 MAPK, which might control distinct forms of synaptic plasticity.

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Figure 1: Activation of extracellular signal-regulated kinase (ERK) by synaptic signalling, and downstream targets.
Figure 2: Extracellular signal-regulated kinase (ERK) activation is required for synaptic plasticity, learning and memory, and increased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) transmission.
Figure 3: Extracellular signal-regulated kinase (ERK) signalling is required for processes that underlie synaptic plasticity.
Figure 4: Parallel mitogen-activated protein kinase (MAPK) cascades might regulate distinct forms of synaptic plasticity.

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Acknowledgements

We thank M. Nuriya and D. Ginty for helpful comments on the manuscript. G.M.T. acknowledges a Wellcome Trust International Prize Travelling Fellowship. Work in the laboratory of R.L.H. is supported by the Howard Hughes Medical Institute and the National Institutes of Health.

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DATABASE

LocusLink

Elk1

ERK1

ERK2

KV4.2

RSK1

RSK2

RSK3

SynGAP

FURTHER INFORMATION

Encyclopedia of Life Sciences

learning and memory

Richard Huganir's homepage

Glossary

LONG-TERM POTENTIATION

(LTP). A possible mechanism for information storage, LTP is a long-lasting strengthening of synaptic responses following specific patterns of 'firing'.

LONG-TERM DEPRESSION

(LTD). An enduring weakening of synaptic strength that is thought to interact with LTP in the cellular mechanisms of learning and memory.

MONOCULAR DEPRIVATION

In mammals, depriving one eye of visual input when neuronal connections between the eyes and visual cortex are forming weakens synaptic connections between these areas. Connections from the 'open' eye populate the area of visual cortex that is normally reserved for the deprived eye. The deprived eye becomes functionally disconnected from the visual cortex, leaving the animal behaviourally blind in this eye, even when visual input is restored.

CREs

Elements in the promoter region of many signal-regulated genes, recognized by CREB family transcription factors.

POSTSYNAPTIC DENSITY

(PSD). In electron micrographs of glutamatergic synapses, an ultrastructural thickening is visible on the postsynaptic side. This PSD can be purified biochemically owing to its resistance to detergents, and is enriched in NMDA-type glutamate receptors, as well as in many scaffold/adaptor proteins and signalling enzymes.

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Thomas, G., Huganir, R. MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5, 173–183 (2004). https://doi.org/10.1038/nrn1346

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