Glial Cells Shape Pathology and Repair After Spinal Cord Injury

Abstract

Glial cell types were classified less than 100 years ago by del Rio-Hortega. For instance, he correctly surmised that microglia in pathologic central nervous system (CNS) were "voracious monsters" that helped clean the tissue. Although these historical predictions were remarkably accurate, innovative technologies have revealed novel molecular, cellular, and dynamic physiologic aspects of CNS glia. In this review, we integrate recent findings regarding the roles of glia and glial interactions in healthy and injured spinal cord. The three major glial cell types are considered in healthy CNS and after spinal cord injury (SCI). Astrocytes, which in the healthy CNS regulate neurotransmitter and neurovascular dynamics, respond to SCI by becoming reactive and forming a glial scar that limits pathology and plasticity. Microglia, which in the healthy CNS scan for infection/damage, respond to SCI by promoting axon growth and remyelination-but also with hyperactivation and cytotoxic effects. Oligodendrocytes and their precursors, which in healthy tissue speed axon conduction and support axonal function, respond to SCI by differentiating and producing myelin, but are susceptible to death. Thus, post-SCI responses of each glial cell can simultaneously stimulate and stifle repair. Interestingly, potential therapies could also target interactions between these cells. Astrocyte-microglia cross-talk creates a feed-forward loop, so shifting the response of either cell could amplify repair. Astrocytes, microglia, and oligodendrocytes/precursors also influence post-SCI cell survival, differentiation, and remyelination, as well as axon sparing. Therefore, optimizing post-SCI responses of glial cells-and interactions between these CNS cells-could benefit neuroprotection, axon plasticity, and functional recovery.

Construction and reconstruction of brain circuits: normal and pathological axon guidance

“…These neurons, which are born embryonically, project their axons contra‐laterally to connect the left and right side of the organism. Together, these commissural networks not only allow for integration and coordination of left‐right neuronal activities, but are essential for the correct processing and interpretation of various sensory information, the coordination of motor responses and other brain functions (Stoeckli ; Gaudet and Fonken ; Ducuing et al ). Many commissural tracts exist in the CNS (Chédotal ).…”

“…The post‐crossing commissural neurons are thus expelled from the midline, and also prevented from re‐crossing the FP. At later stages, they follow rostro‐caudal gradients of guidance cues, turning rostrally or caudally in the ventral or lateral funiculi (Gaudet and Fonken ; Ducuing et al ; Chédotal ).…”

“…Indeed, corticospinal tract (CST) lesions, such as a bilateral pyramidotomy, lead to the complete loss of voluntary movement. Following a spinal cord lesion, extrinsic mechanisms such as growth inhibitors or glial scars, inhibit axonal regeneration (Gaudet and Fonken ). Several inhibitory signaling molecules have since been identified such as Nogo or myelin‐associated glycoproteins (Caroni and Schwab ; McKeon et al ; Afshari et al ; Lang et al ).…”

GABAergic‐astrocyte signaling: A refinement of inhibitory brain networks

“…Astrocytes also encompass a large heterogeneous glial cell type (Matyash & Kettenmann, ; Zhang & Barres, ), including protoplasmic astrocytes, fibrous astrocytes, Müller cells, Bergman glia, perivascular glia, and velate astrocytes, each with particular molecular profiles (Farmer & Murai, ; Matyash & Kettenmann, ; Morel et al, ; Wu, Pan, Zuo, Li, & Hong, ; Zhang et al, ). Accumulated evidence has revealed the tight relationship between astrocytes, neurons, and synapses in the nervous system (Allen & Eroglu, ; Araque, Parpura, Sanzgiri, & Haydon, ; Gaudet & Fonken, ). In particular, astrocytes are recognized as key factors involved in synapse maturation, remodeling, and transmission that finally regulate synaptic plasticity (Araque et al, ; Eroglu & Barres, ; Rusakov, ).…”

“…Accumulated evidence has revealed the tight relationship between astrocytes, neurons, and synapses in the nervous system (Allen & Eroglu, 2017;Araque, Parpura, Sanzgiri, & Haydon, 1999;Gaudet & Fonken, 2018). In particular, astrocytes are recognized as key factors involved in synapse maturation, remodeling, and transmission that finally regulate synaptic plasticity (Araque et al, 2014;Eroglu & Barres, 2010;Rusakov, 2015).…”