Synaptic Plasticity on Motoneurons After Axotomy: A Necessary Change in Paradigm

Abstract

Motoneurons axotomized by peripheral nerve injuries experience profound changes in their synaptic inputs that are associated with a neuroinflammatory response that includes local microglia and astrocytes. This reaction is conserved across different types of motoneurons, injuries, and species, but also displays many unique features in each particular case. These reactions have been amply studied, but there is still a lack of knowledge on their functional significance and mechanisms. In this review article, we compiled data from many different fields to generate a comprehensive conceptual framework to best interpret past data and spawn new hypotheses and research. We propose that synaptic plasticity around axotomized motoneurons should be divided into two distinct processes. First, a rapid cell-autonomous, microglia-independent shedding of synapses from motoneuron cell bodies and proximal dendrites that is reversible after muscle reinnervation. Second, a slower mechanism that is microgliadependent and permanently alters spinal cord circuitry by fully eliminating from the ventral horn the axon collaterals of peripherally injured and regenerating sensory Ia afferent proprioceptors. This removes this input from cell bodies and throughout the dendritic tree of axotomized motoneurons as well as from many other spinal neurons, thus reconfiguring ventral horn motor circuitries to function after regeneration without direct sensory feedback from muscle. This process is modulated by injury severity, suggesting a correlation with poor regeneration specificity due to sensory and motor axons targeting errors in the periphery that likely render Ia afferent connectivity in the ventral horn nonadaptive. In contrast, reversible synaptic changes on the cell bodies occur only while motoneurons are regenerating. This cell-autonomous process displays unique features according to motoneuron type and modulation by local microglia and astrocytes and generally results in a transient reduction of fast synaptic activity that is probably replaced by embryonic-like slow GABA depolarizations, proposed to relate to regenerative mechanisms.

Microglial recruitment and mechanisms involved in the disruption of afferent synaptic terminals on spinal cord motor neurons after acute peripheral nerve injury

“…Microglial activation around axotomized MNs is an extensively documented process, but its effect on afferent synaptic bouton organization has been poorly addressed with rather confusing results. For a long time, it was assumed that activated microglia recruited close to MN cell bodies play a role as “synaptic strippers”; however, whether stripping represents a simple and reversible synaptic withdrawal or, conversely, leads to the degeneration and phagocytosis of synapses, has yet to be clearly established (Aldskogius, 2011; Alvarez et al, 2020; Linda et al, 2000; Möller et al, 1996; Moran & Graeber, 2004; Sumner, 1975). In axotomized facial MNs, Blinzinger and Kreutzberg (1968) have described how active microglia displaced intact synaptic terminals from neuronal perikarya; the absence of degenerating synaptic boutons and lack of apparent phagocytosis by microglia have also been reported.…”

“…The conspicuous structural changes that MN cell bodies suffer after axonal interruption are classically described within the concept of chromatolysis: a retrograde response mainly focused on alterations in the endoplasmic reticulum (ER) and in other organelles (Lieberman, 1971). Nevertheless, peripheral nerve transection also affects the stability of synaptic inputs on the corresponding MN cell bodies (Alvarez et al, 2020; Brannstrom & Kellerth, 1998; Sumner, 1975; Sumner & Sutherland, 1973). Pioneering studies by Blinzinger and Kreutzberg (1968) have shown that the loss of the afferent synaptic boutons on MNs following axotomy is mediated by recruited perineuronal microglial cells, leading to the introduction of the synaptic stripping concept.…”

Long-Term Suppression of c-Jun and nNOS Preserves Ultrastructural Features of Lower Motor Neurons and Forelimb Function after Brachial Plexus Roots Avulsion

“…In the current study, vehicle-treated rats had evidence of astrocytic invasion, synaptic stripping, and intervening spaces between motor neurons and synapses were occupied by astrocytic processes. Astrocytes replace microglia from the surface of motor neurons and synapse recovery following successful regeneration in the periphery coincides with the disappearance of astrocyte wrapping [ 63 ]. In the present study, however, at 6 months, astrocytic processes were still present on the surfaces of surviving motor neurons, especially those with unhealthy ultrastructural appearance.…”

Spinal Reflex Recovery after Dorsal Rhizotomy and Repair with Platelet-Rich Plasma (PRP) Gel Combined with Bioengineered Human Embryonic Stem Cells (hESCs)

“…As a result of the lesion, glutamatergic (VGLUT1) synapses are lost and reorganized, resulting in the disappearance of specific synaptic clusters [ 29 ]. Therefore, through different histological techniques, it was possible to assert that the experimental model used here resulted in the withdrawal of primary afferents.…”

“…The evidence for this was the extensive degeneration in the dorsal column of the spinal cord and a concomitant decrease in immunoreactivity for VGLUT1, which mainly occurred in the superficial laminae and was accompanied by an intense reactivity of glial cells. Microglial reactivity is related to the removal of VGLUT1 synapses in the ventral horn, while such loss mechanism is microglia-independent for the dorsal horn [ 29 ]. These morphological changes were reflected in functional behavior, resulting in the loss of sensibility in the ipsilateral site to the lesion site.…”