Glial Regulation of the Neuronal Connectome through Local and Long-Distant Communication

Abstract

If "the connectome" represents a complete map of anatomical and functional connectivity in the brain, it should also include glia. Glia define and regulate both the brain's anatomical and functional connectivity over a broad range of length scales, spanning the whole brain to subcellular domains of synaptic interactions. This Perspective article examines glial interactions with the neuronal connectome (including long-range networks, local circuits, and individual synaptic connections) and highlights opportunities for future research. Our understanding of the structure and function of the neuronal connectome would be incomplete without an understanding of how all types of glia contribute to neuronal connectivity and function, from single synapses to circuits.

Figure 1

Conduction time between relay points in neural circuits must be precise for spike-timing dependent plasticity and sustaining oscillations over long-distance networks. Myelin is the most effective means of increasing conduction velocity; thus myelin strongly influences network function and by activity-dependent feedback, may contribute to nervous system plasticity. (A) Mouse optic nerve reconstructed from several hundred ultra-thin sections obtained by serial block-face electron microscopy. Such new methods are enabling network analysis of myelination at an ultrastructural level. (B) Optic nerve in cross section analyzed by transmission electron microscopy. Note the multiple layers of compact membrane (myelin) wrapped around axons. (C) Three-dimensional reconstruction of the node of Ranvier from serial block-face electron microscopy, as shown in A. Note the compact myelin (purple) wrapped around the axon (gray), forming a spiral channel of cytoplasm appearing as a series of paranodal loops flanking the node (gold). The electrogenic node of Ranvier, where voltage-gated sodium channels are concentrated, is ensheathed by perinodal astrocytes (blue). Scale bar = 10 um in A, 1 um in B and C.

Figure 2

Astrocytes are intimately associated with tens of thousands of synapses through highly ramified slender branches. Astrocytes can influence neuronal connectivity by binding multiple synapses and multiple neurons into functional assemblies, but astrocytes also operate at a subcellular level to sense and modulate synaptic activity at single synapses. (A) A single astrocyte from the neocortex of an adult mouse; note the cell body, multiple branches, and intricate fine highly-branched terminals. (B) An enlargement and surface rendering of the astrocyte processes shown in (A). Curtesy of Eric Bushong and Mark Ellisman at the National Center for Microscopy and Imaging Research, UCSD. See (Shigetomi et al., 2013) for additional information. The large tick marks are 5 μm in (A) and 0.5 um in (B).

Figure 3

Microglia respond to nervous system damage but also monitor and remove synapses in an activity-dependent manner. (A) Microglia in a resting state in the CA1 area of hippocampus (green, Iba-1), nuclei are blue. (B) Activated microglia in vitro engulfing fluorescent-labeled latex beads. A, from Zhang et al., 2014. B, from Black and Waxman, 2014.