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The molecular basis of CaMKII function in synaptic and behavioural memory

Nature Reviews Neurosciencevolume 3pages175190 (2002) | Download Citation

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Abstract

Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.

Key Points

  • Calcium/calmodulin-dependent protein kinase II (CaMKII) — the main protein of the postsynaptic density — is a Ca2+/calmodulin-activated dodecameric enzyme. One of its main functional properties is its ability to phosphorylate itself. This reaction alters the enzyme such that its activity becomes independent of Ca2+/calmodulin. This property makes CaMKII a good candidate for the storage of long-term synaptic memory.

  • The analysis of long-term potentiation (LTP) has provided the deepest insights into CaMKII function in synaptic physiology. So, CaMKII is activated by Ca2+ entry through the NMDA receptor, and pharmacological and genetic results have shown that CaMKII is necessary and sufficient for the induction of LTP.

  • CaMKII translocates to synapses and binds directly to the NMDA receptor. Like autophosphorylation, this interaction reduces the dependence of CaMKII on Ca2+/calmodulin. CaMKII translocation places it in an ideal situation to control synaptic strength, largely by affecting the functional properties of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, as well as their trafficking and anchoring to the postsynaptic membrane.

  • CaMKII might act as a bistable switch for the long-term storage of synaptic memory. The newest model in this regard takes into account not only the biochemical properties of the enzyme, but also the specific environment that it encounters in the postsynaptic density. Biochemical, pharmacological and electrophysiological data lend support to the model, although definitive proof of its validity is still missing.

  • Progress has been made in understanding how CaMKII contributes to brain function at the systems level. So, eliminating CaMKII phosphorylation interferes with activity-dependent developmental processes and experience-dependent plasticity in vivo. Behavioural tests also show that memory is strongly impaired by interfering with CaMKII function.

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Acknowledgements

We thank G. Fain, N. Otmakhov and R. Malinow for comments on this review. The authors' work is supported by the National Institutes of Health.

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Affiliations

  1. Department of Biology, Brandeis University, Waltham, 02454, Massachusetts, USA

    • John Lisman
  2. Department of Neurobiology, Stanford University School of Medicine, Stanford, 94305, California, USA

    • Howard Schulman
  3. SurroMed Inc., Mountain View, 94043, California, USA

    • Howard Schulman
  4. Cold Spring Harbor Laboratory, Cold Spring Harbor, 11724, New York, USA

    • Hollis Cline

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Correspondence to John Lisman.

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Glossary

POSTSYNAPTIC DENSITY

An electron-dense thickening underneath the postsynaptic membrane at excitatory synapses that contains receptors, structural proteins linked to the actin cytoskeleton and signalling elements, such as kinases and phosphatases.

ALTERNATIVE SPLICING

During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing gives rise to different messages from the same DNA molecule.

HEBB'S RULE

“When the axon of cell A excites cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells so that A's efficiency as one of the cells firing B is increased.”

TETANIC STIMULATION

A train of stimuli in which afferent axons are briefly activated at high frequency. In LTP experiments, a 1-s train of pulses delivered at a frequency of 100 Hz is commonly used to potentiate transmission.

PAIRING PROTOCOL

If a cell is artificially depolarized while low-frequency stimulation is delivered, synaptic transmission will be potentiated because the depolarization relieves the Mg2+-dependent block of NMDA receptors.

DOMINANT NEGATIVE

A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

QUANTAL ANALYSIS

This type of analysis was developed to account for the properties of transmitter release at the neuromuscular junction. It aims to describe release as a function of three basic parameters: the number of release sites (n), the probability of release at each site (p), and the postsynaptic response elicited by a single transmitter vesicle (q). The amplitude of a synaptic event can be described by the product npq. Although quantal analysis provides a valid account of release at the neuromuscular junction, some of its underlying assumptions might not be valid at central synapses.

QUANTAL SIZE

The synaptic response elicited by a single vesicle of transmitter as determined by postsynaptic factors such as the number and affinity of receptors.

FAILURE RATE

The probability that a presynaptic action potential will fail to produce a postsynaptic response.

SILENT SYNAPSE

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

STARGAZIN

A molecule that is involved in the delivery of AMPA-type glutamate receptors to the cell surface. Mice with mutations in this protein — the so-called stargazer mice — arose spontaneously and were detected by their distinctive head-tossing motion and unsteady gait.

DEPOTENTIATION

A reversal of LTP by low-frequency synaptic stimulation. Depotentiation shares some characteristics with long-term depression; both are induced by low-frequency stimulation, and both require NMDA receptor and protein phosphatase activity. However, it is unclear whether they represent the same phenomenon or are fundamentally different.

CIS-ACTING ELEMENT

A regulatory genetic element that is located in the same DNA molecule as the gene that is being regulated.

BARRELS

Cylindrical columns of neurons that are seen in the rodent somatosensory neocortex. Each barrel receives sensory input from a principal whisker follicle, and the topographical organization of the barrels corresponds precisely to the arrangement of whisker follicles on the face.

GENE KNOCK-IN

The insertion of a mutant gene at the exact site of the genome at which the corresponding wild-type gene is located. This approach is used to ensure that the mutant gene is regulated in the same way as the endogenous locus.

PLACE CELLS

Hippocampal principal cells that fire selectively when an animal is in a particular location in its environment, presumably encoding a spatial map of its surroundings.

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 platform. Learning in this task involves the hippocampus.

TETRACYCLINE-DEPENDENT TRANSACTIVATOR SYSTEM

A system that allows the temporal control of gene expression in eukaryotic systems through the administration of tetracycline. It is based on two key elements: the tetracycline-dependent transactivator protein (tTA) and the target gene under the control of a tTA-responsive element. When these elements are transfected into eukaryotic cells, the tTA binds to the tTA-responsive element to initiate transcription. Tetracycline can then be administered to stop expression of the target gene.

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https://doi.org/10.1038/nrn753

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