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  • Review Article
  • Published:

Structural plasticity upon learning: regulation and functions

Key Points

  • Recent advances have provided evidence that the loss of pre-existing synapses and the assembly and retention of new synapses may be integral components of behavioural learning and memory processes.

  • Specific synapse gains and losses have been related conclusively to animal learning and to structural traces of the learning. Causality relationships between the new assembly of identified synapses upon learning and the behavioural expression of the learned memories could be established in at least one case.

  • Learning triggers enhanced synapse turnover, and repeated training produces a selective long lasting retention of some of the new synapses. These are frequently clustered spatially. Mutations in many gene products important for synapse stabilization are associated with mental retardation and psychiatric conditions.

  • Long-term potentiation experiments in slice cultures have revealed that new synapses tend to be retained in spatial clusters, suggesting mechanisms of local co-regulation for synapses that may involve the same or related learning-related memories.

  • Behaviourally related synapses are assembled and lost within spatially close (<2 μm) stretches of dendrites in vivo, suggesting that they may encode specific memories.

  • Enhanced plasticity promoting learning, for example, upon environmental enrichment, involves higher rates of both synapse assembly and disassembly. The presence of larger numbers of dynamic synapses before learning may facilitate learning.

  • Reducing inhibition enhances plasticity, and augmenting inhibition closes critical periods of increased plasticity during early postnatal life. Likewise, enhancing excitation also enhances plasticity. In the adult, plasticity is reduced by molecular mechanisms that function as 'brakes' on plasticity.

  • Structural plasticity involving inhibitory neurons can precede that by excitatory neurons and may have a critical role in regulating circuit plasticity during learning. Mechanisms regulating plasticity during critical periods of development and in the adult may involve similar major roles for inhibitory connectivity regulation.

  • Challenges for future research include: defining the relationships between gains and losses of identified individual synapses upon learning, and the memory of what was learned at the microcircuit and systems level; and relating genes involved in psychiatric conditions to synapse and microcircuit remodelling upon learning under control and disease conditions.

  • Future progress will depend on methods to monitor the structure and function of synaptic networks in vivo, as well as on the development of synaptic network models that combine changes in synaptic function and connectivity.

Abstract

Recent studies have provided long-sought evidence that behavioural learning involves specific synapse gain and elimination processes, which lead to memory traces that influence behaviour. The connectivity rearrangements are preceded by enhanced synapse turnover, which can be modulated through changes in inhibitory connectivity. Behaviourally related synapse rearrangement events tend to co-occur spatially within short stretches of dendrites, and involve signalling pathways partially overlapping with those controlling the functional plasticity of synapses. The new findings suggest that a mechanistic understanding of learning and memory processes will require monitoring ensembles of synapses in situ and the development of synaptic network models that combine changes in synaptic function and connectivity.

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Figure 1: Molecular mechanisms regulating activity-mediated stabilization of dendritic spines.
Figure 2: Learning-induced structural rewiring of synaptic networks.
Figure 3: Global and local synapse turnover regulation processes affecting learning and memory.
Figure 4: Mechanisms of structural metaplasticity regulation.
Figure 5: Circuit mechanisms of plasticity regulation.

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Acknowledgements

This work was supported by the Synapsy NCCR of the Swiss National Science Foundation.

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Correspondence to Pico Caroni.

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Glossary

Synapse dynamics

Excitatory synapses at spines exhibit several forms of structural plasticity regulated by activity, including changes in the size of pre- and postsynaptic complexes, and spine disappearance and appearance events.

Spine dynamics

The spines of excitatory synapses exhibit structural plasticity, including changes in shape and size and spine disappearance and appearance events.

Fragile X syndrome

X-linked syndrome caused by triplet repeat expansions (CGG) resulting in reduced expression of FMR1 (fragile X mental retardation 1). The mutations are the most common single-gene cause of autism and intellectual disability.

Memory consolidation

The processes through which memory traces become long lasting. Synaptic consolidation mechanisms include protein synthesis-dependent long-term potentiation and structural plasticity.

Critical period

A developmental period of enhanced plasticity during early postnatal life whose opening and closing is regulated by experience. Learning during critical periods can leave long-lasting structural traces that influence adult learning.

Innate natural circuits

Connectivity that may support innate processing such as tuning to positions or orientations in space or matching visual and auditory inputs. Adaptive alternative circuits can be assembled during critical periods and retained in the adult.

Fluoxetine

A selective serotonin reuptake inhibitor used to treat major depression (trade names include Prozac; Eli Lilly) that can enhance plasticity in the adult.

Perineuronal nets

Specialized extracellular matrix surrounding soma and proximal dendrites of parvalbumin-positive interneurons. The assembly of perineuronal nets correlates with local closure of critical periods, and their removal reactivates plasticity in the adult.

Receptive fields

In the visual system, these are the regions to which a neuron responds effectively to the presence of a stimulus. More generally, neurons in sensory systems are selectively tuned to particular stimuli from the environment.

Rett syndrome

Neurodevelopmental disorder caused by mutations of MECP2 (methyl-CpG-binding protein 2), a methylated DNA binding protein that maps onto the X chromosome. Some of the manifestations of Rett syndrome are characteristic of autism spectrum disorders.

Microcircuit

The minimal number of interacting defined neurons that can collectively produce a particular functional output. The term implies local computations, and usually distinguishes locally interconnected neurons (for example, within the hippocampus or within its dentate gyrus) from the long-range projections that interconnect brain regions.

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Caroni, P., Donato, F. & Muller, D. Structural plasticity upon learning: regulation and functions. Nat Rev Neurosci 13, 478–490 (2012). https://doi.org/10.1038/nrn3258

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