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Structural plasticity and memory

Key Points

  • Much evidence indicates that the formation of long-term memory involves enduring alteration of synaptic responses to the learned stimulus. These changes subserve memory storage and ensure its retrieval. A central question derived from these observations is, what are the cellular and molecular events that lead to such changes?

  • Recent findings show that behavioural learning or the artificial form of synaptic plasticity known as long-term potentiation (LTP) results in morphological changes in excitatory synapses at dendritic spines. Changes in spine morphology could alter postsynaptic responses to extracellular stimulation, such as changes in calcium influx and calcium storage, changes in synaptic transmission, and induction of local protein synthesis. These cellular events are postulated to contribute to changes in synaptic efficacy underlying learning.

  • The architecture of spines, and therefore their ability to change shape, depends on the specialized underlying structure of the cytoskeletal filaments. Studies have shown that LTP induces alterations in actin polymerization in spines. Moreover, inhibition of actin polymerization suppresses LTP.

  • Activation of glutamate receptors in the spine induces actin-dependent modulation of spine morphology. Glutamate contributes to the initial actin-dependent spine motility and also to events that lead to spine stability. Evidence indicates that AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors contribute to actin-dependent spine stabilization. Increases in AMPA receptors at the synapse (observed after stimulation that leads to long-term plasticity) could contribute to the stabilization of spine morphology.

  • Rho GTPases mediate actin cytoskeleton-dependent neuronal morphogenesis and might be activated by glutamate and adhesion molecules. Recent findings have shown a central role for the Rho GTPase pathway in memory formation and synaptic plasticity.

  • Adhesion molecules also modulate spine morphology by regulating actin cytoskeleton. Such molecules have been shown to be involved in long-term memory and LTP formation.

  • Together, these observations indicate a model in which glutamate transmission and adhesion molecules regulate neuronal morphogenesis initiated by stimulation that leads to LTP and long-term memory. These structural changes are mediated and stabilized by the Rho GTPases and the actin cytoskeleton. Alterations in synaptic morphology and stabilization of these changes are hypothesized to be involved in memory consolidation and persistence.

Abstract

Much evidence indicates that, after learning, memories are created by alterations in glutamate-dependent excitatory synaptic transmission. These modifications are then actively stabilized, over hours or days, by structural changes at postsynaptic sites on dendritic spines. The mechanisms of this structural plasticity are poorly understood, but recent findings are beginning to provide clues. The changes in synaptic transmission are initiated by elevations in intracellular calcium and consequent activation of second messenger signalling pathways in the postsynaptic neuron. These pathways involve intracellular kinases and GTPases, downstream from glutamate receptors, that regulate and coordinate both cytoskeletal and adhesion remodelling, leading to new synaptic connections. Rapid changes in cytoskeletal and adhesion molecules after learning contribute to short-term plasticity and memory, whereas later changes, which depend on de novo protein synthesis as well as the early modifications, seem to be required for the persistence of long-term memory.

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Figure 1: Molecular mechanisms involved in the initiation and maintenance of synaptic plasticity.
Figure 2: Long-term potentiation (LTP) or learning induces morphological changes in dendritic spines.
Figure 3: Methods used to monitor changes in dendritic spines following long-term potentiation (LTP) or learning.
Figure 4: Actin cytoskeleton is involved in spine morphogenesis.
Figure 5: Long-term potentiation (LTP) and behavioural experience induce glutamate receptor trafficking into spines.
Figure 6: Rho GTPaseas mediate extracellular stimulation-induced actin cytoskeleton rearrangements.

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Acknowledgements

This work was supported by NIH grants and by an NSF grant.

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Correspondence to Joseph LeDoux.

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FURTHER INFORMATION

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dendritic spines

learning and memory

protein synthesis and long-term synaptic plasticity

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Glossary

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. LTP is considered to be a cellular model of learning and memory. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic cell population spike. LTP has also been used to study memory mechanisms in other brain regions, such as the amygdala and areas of the cerebral cortex.

BACK-PROPAGATING ACTION POTENTIALS

Although action potentials typically travel down the axon towards the presynaptic terminal, they can also be initiated at the cell body and propagate back into the dendrites, thereby shaping the integration of synaptic activity and influencing the induction of synaptic plasticity.

TWO-PHOTON MICROSCOPY

A form of microscopy in which a fluorochrome that would normally be excited by a single photon is stimulated quasi-simultaneously by two photons of lower energy. Under these conditions, fluorescence increases as a function of the square of the light intensity, and decreases as the fourth power of the distance from the focus. Because of this behaviour, only fluorochrome molecules near the plane of focus are excited, greatly reducing light scattering and photodamage of the sample.

FEAR CONDITIONING

A form of Pavlovian (classical) conditioning in which the animal learns that an innocuous stimulus (for example, an auditory tone — the conditioned stimulus or CS), comes to reliably predict the occurrence of a noxious stimulus (for example, foot shock — the unconditioned stimulus or US) following their repeated paired presentation. As a result of this procedure, presentation of the CS alone elicits conditioned fear responses.

CADHERINS

Calcium-dependent cell adhesion molecules that tend to engage in homophilic interactions.

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Lamprecht, R., LeDoux, J. Structural plasticity and memory. Nat Rev Neurosci 5, 45–54 (2004). https://doi.org/10.1038/nrn1301

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