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Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS

Abstract

Almost 60 years have passed since the initial discovery by Hubel and Wiesel that changes in neuronal activity can elicit developmental rewiring of the central nervous system (CNS). Over this period, we have gained a more comprehensive picture of how both spontaneous neural activity and sensory experience-induced changes in neuronal activity guide CNS circuit development. Here we review activity-dependent synaptic pruning in the mammalian CNS, which we define as the removal of a subset of synapses, while others are maintained, in response to changes in neural activity in the developing nervous system. We discuss the mounting evidence that immune and cell-death molecules are important mechanistic links by which changes in neural activity guide the pruning of specific synapses, emphasizing the role of glial cells in this process. Finally, we discuss how these developmental pruning programmes may go awry in neurodevelopmental disorders of the human CNS, focusing on autism spectrum disorder and schizophrenia. Together, our aim is to give an overview of how the field of activity-dependent pruning research has evolved, led to exciting new questions and guided the identification of new, therapeutically relevant mechanisms that result in aberrant circuit development in neurodevelopmental disorders.

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Fig. 1: Model circuits for studying activity-dependent synaptic pruning.
Fig. 2: Glial cell engulfment mechanisms that regulate synaptic pruning.
Fig. 3: Cell death molecules involved in synaptic pruning.
Fig. 4: Synaptic pruning and neurodevelopmental disorders.

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Acknowledgements

The authors thank P. Feinberg for his careful review of the manuscript. This work was supported by grant numbers NIMH-R01MH113743 and NINDS-R01NS117533 (D.P.S.) and NINDS-F31NS117053 (G.G.).

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The authors contributed equally to all aspects of the article.

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Correspondence to Dorothy P. Schafer.

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Nature Reviews Neuroscience thanks M. Freeman, M. Kano, M. Matteoli and A. Schaeffer for their contribution to the peer review of this work.

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Glossary

Synaptic pruning

Developmental elimination of elements that comprise a bona fide structural synapse (presynaptic terminal and postsynaptic membranes), which might also include some pruning of small branches of axonal arbors and dendrites, while remaining synapses are maintained and strengthened.

Spontaneous neural activity

Neuronal activity that is not driven by an external stimulus.

Experience-driven neural activity

Neuronal activity driven by external changes affecting sensory experience.

Eye-specific segregation

A process involving synaptic pruning by which spontaneous retinal activity drives presynaptic inputs from retinal ganglion cells to segregate and synapse in discrete, non-overlapping territories within the lateral geniculate nucleus during postnatal development.

Monocular deprivation

The loss of sensory input to one eye, typically performed by suturing one eye closed for a defined period.

Ocular dominance plasticity

A process by which monocular deprivation results in strengthening of synaptic inputs from the open eye and weakening and elimination of synapses corresponding to the sutured, deprived eye.

Long-term depression

(LTD). A process by which changes in neuronal activity, such as sustained low-frequency stimulation, induce a reduction in synaptic strength.

Engulfment

The internalization or phagocytosis of material by a cell for degradation.

Trogocytosis

Partial phagocytosis of membrane material (trogo means ‘nibble’) while leaving the remaining membrane intact.

Apoptosis

A canonical highly regulated process of programmed cell death that occurs in multiple contexts, including during development, and involves membrane blebbing, cell shrinkage and DNA fragmentation.

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Faust, T.E., Gunner, G. & Schafer, D.P. Mechanisms governing activity-dependent synaptic pruning in the developing mammalian CNS. Nat Rev Neurosci 22, 657–673 (2021). https://doi.org/10.1038/s41583-021-00507-y

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