How does PKMζ maintain long-term memory?

Abstract

Most of the molecular mechanisms contributing to long-term memory have been found to consolidate information within a brief time window after learning, but not to maintain information during memory storage. However, with the discovery that synaptic long-term potentiation is maintained by the persistently active protein kinase, protein kinase Mζ (PKMζ), a possible mechanism of memory storage has been identified. Recent research shows how PKMζ might perpetuate information both at synapses and during long-term memory.

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Figure 1: PKMζ formation in LTP.
Figure 2: Mechanism of synaptic potentiation by PKMζ in LTP maintenance.
Figure 3: Model of PKMζ synaptic autotagging in memory maintenance.

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Acknowledgements

This research was supported by the US National Institutes of Health (NIH) (grants R01 MH53576 and MH57068). The article is dedicated to the memory of the late James H. Schwartz, a pioneer in the study of persistent kinases and memory25.

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Consolidated long-term memories disrupted by PKMζ inhibition (PDF 184 kb)

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Glossary

Cellular memory consolidation

The molecular mechanisms that convert memories into an enduring form. The process typically lasts for a few hours after learning and is associated with new protein synthesis. It is distinct from systems memory consolidation, which involves shifts in the neuronal circuitry that subserves a memory and can take weeks or longer.

Long-term memory storage

The physiological mechanism in the brain that perpetuates enduring memories. The storage phase of long-term memory begins from a few hours to a day after learning and can last a lifetime.

Long-term potentiation

A persistent enhancement of excitatory synaptic transmission lasting hours to days, triggered by strong, typically high-frequency, afferent stimulation of the synapse. It is widely studied as a putative physiological basis of long-term memory.

PDZ domain

A common protein structural motif that interacts with specific carboxy-terminal sequences of other proteins. The intracellular distribution and trafficking of many proteins are regulated by their binding to PDZ domain-containing proteins.

Postsynaptic density

A cytoskeletal specialization of the synapse identified by electron microscopy as an electron-dense region at the membrane of the postsynaptic neuron. It concentrates and organizes neurotransmitter receptors, receptor-binding proteins and postsynaptic signalling molecules.

Synaptic tagging

A hypothesis to explain the potentiation during late-LTP (long-term potentiation) of activated synapses by proteins newly synthesized in the neuronal cell body or dendrite. Afferent stimulation sets up a 'tag' specifically at activated synapses that captures the newly synthesized plasticity-related proteins.

Trace eye-blink conditioning

A form of classical conditioning in which the conditioned stimulus (CS; typically an auditory or visual stimulus) precedes the unconditioned stimulus (US; an eye-blink-eliciting stimulus such as a puff of air to the cornea) by a stimulus-free period (trace interval). Trace eye-blink conditioning requires both an intact cerebellum and hippocampus.

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Sacktor, T. How does PKMζ maintain long-term memory?. Nat Rev Neurosci 12, 9–15 (2011). https://doi.org/10.1038/nrn2949

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