Engulfed by Glia: Glial Pruning in Development, Function, and Injury across Species

Abstract

Phagocytic activity of glial cells is essential for proper nervous system sculpting, maintenance of circuitry, and long-term brain health. Glial engulfment of apoptotic cells and superfluous connections ensures that neuronal connections are appropriately refined, while clearance of damaged projections and neurotoxic proteins in the mature brain protects against inflammatory insults. Comparative work across species and cell types in recent years highlights the striking conservation of pathways that govern glial engulfment. Many signaling cascades used during developmental pruning are re-employed in the mature brain to "fine tune" synaptic architecture and even clear neuronal debris following traumatic events. Moreover, the neuronglia signaling events required to trigger and perform phagocytic responses are impressively conserved between invertebrates and vertebrates. This review offers a compare-and-contrast portrayal of recent findings that underscore the value of investigating glial engulfment mechanisms in a wide range of species and contexts.

Faulty autolysosome acidification in Alzheimer’s disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

“…Even at a relatively late stage of compromise, intracellular Aβ-immunoreactive fibrils forming a perinuclear core are mainly contained within membrane-bound tubular structures derived from fusion of Aβ-positive ALs. This stage can be reached without appreciable microglial or astrocytic invasion that would reflect ‘eat me’ signaling from dying neurons 42 , 43 , implying, therefore, that neuronal structural integrity is prolonged even as PANTHOS is quite advanced. Subsequent microglial and astrocytic invasion of the PANTHOS neuron heralds the eventual cell death that converts this amyloid lesion within an intact neuron into an extracellular amyloid plaque.…”

Oligodendrocyte precursor cells prune axons in the mouse neocortex

“…Consolidation of nascent networks into stable, but adaptable, circuits requires extensive remodeling during development, when excess neurons, axon collaterals and even individual synapses are removed 1,44,45 . This structural refinement is aided by glia, which recognize and engulf both cellular debris and portions of intact neurons 46,47 . Microglia are key participants in this process, as they express phagocytic genes (e.g.…”

Charging Up the Periphery: Glial Ionic Regulation in Sensory Perception

“…Analogously, the C. elegans sense-organ amphid sheath glia secretes the TSP-1 domain containing protein FIG-1 to modulate sensory neuron properties ( Bacaj et al, 2008 ). Vertebrate astrocytes use the MEGF10 and MERTK phagocytic pathway to mediate synapse elimination ( Chung et al, 2013 ), while Drosophila astrocytes similarly deploy the MEGF10 ortholog Draper to clear synaptic and neuronal debris following injury ( MacDonald et al, 2006 ; Hilu-Dadia and Kurant, 2020 ; Raiders et al, 2021b ) and C. elegans peripheral sense organ glia use a similar (albeit not identical) machinery to regulate sensory neuron shape and animal behavior ( Raiders et al, 2021a ).…”