(Re)building the nervous system: A review of neuron-glia interactions from development to disease

Abstract

Neuron-glia interactions are fundamental to the development and function of the nervous system. During development, glia, including astrocytes, microglia, and oligodendrocytes, influence neuronal differentiation and migration, synapse formation and refinement, and myelination. In the mature brain, glia are crucial for maintaining neural homeostasis, modulating synaptic activity, and supporting metabolic functions. Neurons, inherently vulnerable to various stressors, rely on glia for protection and repair. However, glia, in their reactive state, can also promote neuronal damage, which contributes to neurodegenerative and neuropsychiatric diseases. Understanding the dual role of glia-as both protectors and potential aggressors-sheds light on their complex contributions to disease etiology and pathology. By appropriately modulating glial activity, it may be possible to mitigate neurodegeneration and restore neuronal function. In this review, which originated from the International Society for Neurochemistry (ISN) Advanced School in 2019 held in Montreal, Canada, we first describe the critical importance of glia in the development and maintenance of a healthy nervous system as well as their contributions to neuronal damage and neurological disorders. We then discuss potential strategies to modulate glial activity during disease to protect and promote a properly functioning nervous system. We propose that targeting glial cells presents a promising therapeutic avenue for rebuilding the nervous system.

Keywords: astrocyte; brain development and function; glial dysfunction; microglia; neurodegenerative and neuropsychiatric disorders; oligodendrocyte.

FIGURE 1

Key steps in CNS development and glial contributions. (a) Progenitor cells and migration. Radial glial cells originating from neural tube neuroepithelial cells generate various cell types, including neurons, astrocytes, and oligodendrocytes, which then migrate to their specified locations. Microglia precursors infiltrate the CNS. (b) Formation of synapses. Following dendritic and axonal growth, synaptic connections are formed. This process is promoted by microglia and astrocytes. (c) Synapse refinement. Synapses will then undergo either strengthening or elimination. Microglia and astrocytes contribute to synapse elimination through synapse engulfment. (d) Myelination. Oligodendrocytes provide myelin sheaths to wrap axons for proper conductance of electric signals in the nervous system. Microglia and astrocytes regulate this process as well. ePS: Exposed phosphatidylserine. Created with Biorender.com.

FIGURE 2

The role of glial cells in adult brain homeostasis, plasticity, and neurogenesis. (a) Glial cells regulate the blood–brain barrier and neurovascular unit and are functionally coupled to neurons to sustain metabolic homeostasis. (b) Glial cells contact neurons to support synaptic function and plasticity. Synaptic functions can be controlled by microglia via the release of cytokines and trophic factors, and astrocytes through the regulation of gliotransmitters such as D‐serine and lactate. Oligodendrocytes further contribute to proper neuronal function as they can modulate axonal conduction by controlling myelin thickness and regulating Ranvier nodes. (c) The potential for adult neurogenesis is tightly regulated by glial cells in an inhibitory manner by pro‐inflammatory cytokine release or in a supportive manner by the release of neurotrophic factors. Created with Biorender.com.

FIGURE 3

Susceptibility for neuronal injury and low recovery potential mediated by glia. (a) Reactive microglia and astrocytes contribute to neuronal susceptibility to neuronal injury by withdrawing supportive factors such as trophic factors and antioxidants and secreting growth inhibitors, which further exacerbate neuronal sensitivity to oxidative stress. Improper glutamate buffering by astrocytes may also amplify neuronal susceptibility to excitotoxic insult. Additionally, microglial phagocytosis may increase because of increased phosphatidyl serine exposure. (b) During injury or disease, secreted factors from glial scars result in the upregulation of several inhibitory molecules, which further compromise the ability for regeneration and recovery of damaged neurons. Oligodendrocytes also increase neuronal susceptibility as they may withdraw key myelinating activities during injury or disease. GSH, glutathione; PS, phosphatidylserine; ROS, reactive oxygen species. Created with Biorender.com.

FIGURE 4

Glial cells contribute to neurodegeneration and nervous system dysfunction. (a) Reactive microglia present in neurodegenerative or neuropsychiatric diseases contribute to neuronal loss and dysfunction by secreting pro‐inflammatory cytokines and activating pro‐inflammatory signaling pathways such as STING and NLRP3. Microglia also contribute to synapse loss and dysfunction through aberrant complement‐mediated phagocytosis. (b) Astrocytes become reactive during neurodegeneration and in neuropsychiatric diseases and this toxic phenotype results in compromised metabolic/trophic support and increased pro‐inflammatory signaling and phagocytosis. (c) Oligodendrocytes affected by disorders of the nervous system reduce their ability to properly myelinate axons, a process that is further disrupted by reactive microglia or astrocytes. Created with Biorender.com.

FIGURE 5

Targeting glial cells to rebuild the nervous system. (a) Blocking microglia or astrocyte conversion to non‐physiological phenotype offers neuronal protection through inhibiting pro‐inflammatory cytokine release (NLRP3, STING) and reducing inappropriate complement‐mediated (C3, C1q, C5) phagocytosis of synapses. (b) Targeting oligodendrocytes and their interactions with reactive glial cells promotes increases in myelination. A reduction in vascular damage or pro‐inflammatory cytokines secretion associated with reactive glia can lead to increases in pro‐myelination signals including MBP, CNTF, and Opn. (c) Modulation of glial cell activities demonstrates the potential to enhance neuronal regeneration and improve NPC migration and neurogenesis. Targeting microglia or astrocytes to stimulate the release of trophic factors such as NGF, IGF‐1, and BDNF may promote neuronal regeneration. Increasing signaling molecules from astrocytes such as SDF1α, CNTF, D‐serine, and BDNF may improve neurogenesis. Neuronal regeneration and neurogenesis may also be enhanced through a reduction of pro‐inflammatory molecules such as IL‐1β and TNFα released from microglia and astrocytes. Created with Biorender.com.