Oligodendrocyte precursor cells prune axons in the mouse neocortex

Abstract

Neurons in the developing brain undergo extensive structural refinement as nascent circuits adopt their mature form. This transformation is facilitated by the engulfment and degradation of excess axonal branches and inappropriate synapses by surrounding glial cells, including microglia and astrocytes. However, the small size of phagocytic organelles and the complex, highly ramified morphology of glia has made it difficult to determine the contribution of these and other glial cell types to this process. Here, we used large scale, serial electron microscopy (ssEM) with computational volume segmentation to reconstruct the complete 3D morphologies of distinct glial types in the mouse visual cortex. Unexpectedly, we discovered that the fine processes of oligodendrocyte precursor cells (OPCs), a population of abundant, highly dynamic glial progenitors, frequently surrounded terminal axon branches and included numerous phagolysosomes (PLs) containing fragments of axons and presynaptic terminals. Single- nucleus RNA sequencing indicated that cortical OPCs express key phagocytic genes, as well as neuronal transcripts, consistent with active axonal engulfment. PLs were ten times more abundant in OPCs than in microglia in P36 mice, and declined with age and lineage progression, suggesting that OPCs contribute very substantially to refinement of neuronal circuits during later phases of cortical development.

Petascale neural circuit reconstruction: automated methods

“…A larger training set generally leads to higher accuracy, but ground truth is laborious to generate. To save labor, we reused 943 μm 3 of ground truth from pilot datasets of the MICrONS project (N. L. Casey M. Schneider-Mizell et al, 2020;Buchanan et al 2021;Sven Dorkenwald et al 2019). A boundary detector pretrained on this old ground truth turned out to generalize well to the new dataset.…”

“…Using the method outlined in (Lee et al 2017), we trained a convolutional network to estimate inter-voxel affinities that represent the potential for neuronal boundaries between adjacent image voxels. The network was pretrained using manually annotated ground truth from previously collected cortical datasets (N. L. Sven Dorkenwald et al 2019;Buchanan et al 2021;Casey M. Schneider-Mizell et al, 2020), then finetuned on a mix of ground truth collected from this dataset, as well as the previous cortical datasets. We made modifications in network architecture, auxiliary tasks, and data augmentation during training as follows.…”

Mechanisms Underlying Target Selectivity for Cell Types and Subcellular Domains in Developing Neocortical Circuits

“…The roles of additional cortical cell types, like microglia, astrocytes and oligodendrocyte precursor cells, in establishing cell-typebiased connections in the cortex remain underexplored. Glial cells may mediate specific synapse growth or elimination (Schafer and Stevens, 2015;Bosworth and Allen, 2017;Stogsdill and Eroglu, 2017;Buchanan et al, 2021). Furthermore, just as radial glia guide axon growth directions in the cortex, glial cells may act directly to guide cortical synaptic partners to each other, as has been observed for cerebellar Bergmann glia (Ango et al, 2008).…”

Glia-Driven Brain Circuit Refinement Is Altered by Early-Life Adversity: Behavioral Outcomes

“…Reduced proliferation of astrocytes and/or disruption to astrocytic activity weakens mature synapses, prevents synapse maturation, and reduces synaptic pruning. Finally, oligodendrocyte precursor cells share the capacity to engulf synapses and aid in synaptic pruning (Buchanan et al, 2021 ). Interestingly, the proliferation, migration, and activity of OPCs bear a striking similarity to microglia.…”