Mechanisms and consequences of microglial responses to peripheral axotomy

Abstract

Microglia respond rapidly to injury of peripheral nerve axons (axotomy). This response is integrated into the responses of the injured neurons, i.e. processes for neuron survival, axon regeneration and restoration of target contact. The microglial response is also integrated in changes in presynaptic terminals on axotomized motor or autonomic neurons and in changes in the central terminals of peripherally axotomized sensory neurons. Microglia also has an established role in interacting with astrocytes to shape their response to peripheral axotomy. Axotomy models in mice have demonstrated a role for microglia in regulating the entry of lymphocytes into motor nuclei or sensory areas following peripheral axotomy. Whether this is a universal component of peripheral nerve injury remains to be determined. Under certain circumstances, microglia activated by axotomy are major contributors to CNS pathology, e.g. in models of neuropathic pain. However, the general roles played by microglia after peripheral nerve injury are still incompletely understood. Early proposals that the microglial reaction to peripheral nerve injury is preparatory for the eventuality of neuron degeneration may still have relevance.

Spinal motor circuit synaptic plasticity after peripheral nerve injury depends on microglia activation and a CCR2 mechanism

“…Microglia become activated around MNs after PNI, but their exact roles in MNs survival, motor axon regeneration, synapse removal, and remodeling the central projections of peripherally injured sensory afferents have been remarkably difficult to elucidate with precision (Aldskogius, 2011). In their pioneering study, Figure 8.…”

“…After PNI, several coincident phenomena occur around cell bodies of axotomized MNs and sensory neurons: (1) activated microglia surround MNs; (2) blood-borne immune cells surround sensory neurons; and (3) synapses become displaced from axotomized MN cell bodies (Blinzinger and Kreutzberg, 1968;Svensson and Aldskogius, 1993;Aldskogius et al, 1999;Cullheim and Thams, 2007;Aldskogius, 2011;Niemi et al, 2013). The significance of these phenomena and their relation to the disappearance of Ia synapses are not clear.…”

Changes in microglial activation within the hindbrain, nodose ganglia, and the spinal cord following subdiaphragmatic vagotomy

“…These agents include cytokines, chemokines, nitric oxide, prostaglandins, and growth factors [23;32;33]. Through release of these agents, activated microglia contribute to the development and maintenance of neuropathic pain [1;24;27;34;44;49]. Previous reports indicate that spinal nerve damage results in activation of microglia in ipsilateral segments of the spinal cord (SC) dorsal horn containing the central terminals of the damaged nerve.…”

Neuropathic pain following traumatic spinal cord injury: Models, measurement, and mechanisms

“…Evidence for the latter in mediating neuropathic pain comes from behavioral recovery after connexin‐43 inhibition (Lee‐Kubli et al, ). Microgliosis, which has been strongly linked to neuropathic pain after peripheral nerve injury (Coull et al, ; Aldskogius, ; Aldskogius and Kozlova, ; Mika et al, ; Tsuda et al, ; Guan et al, ), also occurs both within the spinal cord remote from the lesion (Detloff et al, ; Gwak and Hulsebosch, ; Gwak et al, ; Kato et al, ) and in supraspinal structures such as thalamus, hippocampus, and cortex (Wu et al, ). Indeed a great deal of emphasis has been placed on the role of microglia in pain following peripheral nerve injury because of their role in spinal disinhibition; activated microglia upregulate brain‐derived neurotrophic factor, which is thought to downregulate the potassium/chloride cotransporter KCC2 in spinal nociceptive neurons.…”