Dendritic shrinkage after injury: a cellular killer or a necessity for axonal regeneration?

Abstract

Dendrites form an essential component of the neuronal circuit have been largely overlooked in regenerative research. Nevertheless, subtle changes in the dendritic arbors of neurons are one of the first stages of various neurodegenerative diseases, leading to dysfunctional neuronal networks and ultimately cellular death. Maintaining dendrites is therefore considered an essential neuroprotective strategy. This mini-review aims to discuss an intriguing hypothesis, which postulates that dendritic shrinkage is an important stimulant to boost axonal regeneration, and thus that preserving dendrites might not be the ideal therapeutic method to regain a full functional network upon central nervous system damage. Indeed, our study in zebrafish, a versatile animal model with robust regenerative capacity recently unraveled that dendritic retraction is evoked prior to axonal regrowth after optic nerve injury. Strikingly, inhibiting dendritic pruning upon damage perturbed axonal regeneration. This constraining effect of dendrites on axonal regrowth has sporadically been proposed in literature, as summarized in this short narrative. In addition, the review discusses a plausible underlying mechanism for the observed antagonistic axon-dendrite interplay, which is based on energy restriction inside neurons. Axonal injury indeed leads to a high local energy demand in which efficient axonal energy supply is fundamental to ensure regrowth. At the same time, axonal lesion is known to induce mitochondrial depolarization, causing energy depletion in the axonal compartment of damaged neurons. Mitochondria, however, become mostly stationary after development, which has been proposed as a potential underlying reason for the low regenerative capacity of adult mammals. Per contra, upon reduced neuronal activity, mitochondrial mobility enhances. In this view, dendritic shrinkage after axonal injury in zebrafish could result in less synaptic input and hence, a release of mitochondria within the soma-dendrite compartment that then translocate to the axonal growth cone to stimulate axonal regeneration. If this hypothesis proofs to be correct, i.e. dendritic remodeling serving as fuel for axonal regeneration, we envision a major shift in the research focus within the neuroregenerative field and in the potential uncovering of various novel therapeutic targets.

Keywords: axonal regeneration; central nervous system; dendritic remodeling; energy supply; mitochondrial dynamics; mitochondrial transport; retina; zebrafish.

Figure 1

Schematic representation of the RGC axonal and dendritic growth response in relation to time after ONC in untreated or mTOR/MMP inhibited adult zebrafish. (A) Immediately after injury, retinal synapses degenerate and RGC dendrites retract, depicted as a negative growth response, shown in red. Directly after dendrite shrinkage, RGC axons start to regrow, inducing a positive growth response, shown in green, eventually resulting in optic tectum reinnervation and target contact initiation. This, in turn, triggers the dendrites to shift their negative growth response to a positive one and to establish new synaptic contacts, finally leading to restoration of vision. (B) Retinal mTOR or MMP inhibition prevents retinal synapse degradation and dendrite collapsing after ONC, shown in a grey color for an unchanged growth response. This dendritic preservation consecutively delays the initiation of axonal regrowth, resulting in a retarded optic tectum reinnervation. Here the effect on target contact initiation was not studied. ONC: Optic nerve crush; RGC: retinal ganglion cell; dpi: day(s) post-injury; mTOR: mechanistic target of rapamycin; MMP: matrix metalloproteinases.

Figure 2

Schematic representation of the hypothesis that dendritic shrinkage after optic nerve crush is accompanied by the mobilization of mitochondria, which could be the driving force for axonal regeneration. (A) In normal physiological conditions, most mitochondria in neurons are stationary and accumulate at sites with a high energy need, especially in synapses, where they play an essential role in synapse maintenance and neurotransmission. (B) Axonal injury induces a drop in mitochondrial membrane potential (ΔΨm) in the nearby mitochondria, resulting in mitochondrial depolarization. These dysfunctional mitochondria are not able to produce the necessary energy for growth cone formation. Within our literature-based energy trade-off hypothesis, dendrites then start to retract after axonal injury, which could go hand in hand with mitochondrial reshuffling towards the cell soma, as reduced synaptic input increases mitochondrial mobility. (C) After massive synaptic and dendritic degeneration, these mitochondria end up in the axons where they could reverse the injury-induced energy deficit, thereby enabling growth cone formation and axonal regrowth.