Sculpting neural circuits by axon and dendrite pruning

Abstract

The assembly of functional neural circuits requires the combined action of progressive and regressive events. Regressive events encompass a variety of inhibitory developmental processes, including axon and dendrite pruning, which facilitate the removal of exuberant neuronal connections. Most axon pruning involves the removal of axons that had already made synaptic connections; thus, axon pruning is tightly associated with synapse elimination. In many instances, these developmental processes are regulated by the interplay between neurons and glial cells that act instructively during neural remodeling. Owing to the importance of axon and dendritic pruning, these remodeling events require precise spatial and temporal control, and this is achieved by a range of distinct molecular mechanisms. Disruption of these mechanisms results in abnormal pruning, which has been linked to brain dysfunction. Therefore, understanding the mechanisms of axon and dendritic pruning will be instrumental in advancing our knowledge of neural disease and mental disorders.

Keywords: Wallerian degeneration; axon retraction; circuit refinement; dendrite severing; neurite remodeling; synapse elimination.

Figure 1

Sex hormone regulation of the neurotrophic signal BDNF directs sexually dimorphic axonal maintenance and pruning. During early mammary gland development in the mouse (E12.5), TrkB⁺ axons receive trophic support from BDNF-expressing mammary mesenchyme in both males and females. At E13 androgens in males induce expression of a truncated form of the TrkB receptor (TrkB.T1) by the mammary mesenchyme. TrkB.T1 sequesters BDNF, neutralizing BDNF signaling. As a result, sensory axons in males are deprived of neurotrophic support and are rapidly pruned (E13.5).

Figure 2

Antagonistic signals regulate climbing fiber refinement. C1ql1/Bai3, and Sema3A/PlexinA4 signaling promote maintenance and strengthening of synapses by acting through receptors expressed by the postsynaptic Purkinje Cell (PC) and presynaptic climbing fiber (CF), respectively. At earlier phases (P7 to P14), AMPA receptor-mediated PC neural activity, driven by CFs, promotes elimination of weaker climbing fibers by an as yet unclear mechanism involving P/Q-type Voltage Gated Calcium Channels (VGCC) that is modulated by gabaergic inhibition. Later (Late phase II, from P15 onward), activation of mGluR1 signaling by neural activity in the Parallel Fiber-PC circuit becomes the main driver for elimination of weaker CFs. This mGluR1 signaling cascade promotes the PC expression of Sema7A that, in turn, acts through presynaptic receptors Integrin β1 and also PlexinC1.

Figure 3

Spatiotemporal control of pruning. Three examples of spatiotemporal control strategies are presented. (a) Expression of the axonal repellent Sema3F (green) commences at P25 and is restricted to neuropeptide Y (NPY)⁺ interneurons in the infrapyramidal region, resulting in pruning of the infrapyramidal tract (IPT) alone while sparing the main bundle (MB) of the mossy fibers. (b) Caspase-dependent signaling is regulated at multiple levels so as to restrict its activity to the degenerating axon (blue box) without triggering cell death or dendritic pruning (yellow box). (c) Calcium influx in specific dendritic branches acts as a spatial and temporal cue to trigger pruning in Drosophila. Intrinsic excitability increases locally, activating calcium influx via voltage-gated calcium channels (VGCCs), which results in the activation of the calcium-activated protease calpain. Abbreviations: CA3, cornu ammonis 3; DG, dentate gyrus.

Figure 4

Parallels and distinctions between degeneration-like pruning and Wallerian degeneration. Despite broad similarities (blue box), as we investigate deeper into the mechanisms of these regressive events clear molecular distinctions arise (yellow box).