Glial Draper signaling triggers cross-neuron plasticity in bystander neurons after neuronal cell death
Preprint posted on 10 April 2023 https://www.biorxiv.org/content/10.1101/2023.04.09.536190v1
A novel form of neuronal plasticity - when a neuron is injured, their healthy neighbour takes up the slack.
Selected by Matthew Davies
Categories: cell biology, developmental biology, neuroscience
Background
The extensive ability of the brain to remodel neuronal connections, termed plasticity, is critical for correct development, learning, and response to injury. A multitude of plasticity mechanisms exist (Magee and Grienberger 2020; Citri and Malenka 2008). One form, which the authors of this preprint term “cross-neuron plasticity”, refers to functional compensation by a “bystander” neuron in response to the death of a neighbouring neuron.
Cross-neuron plasticity has been described across the animal kingdom (Hoffman 1950; Parnas et al. 1984; Modney and Muller 1994), including at the Drosophila neuromuscular junction (NMJ; Hsu et al. 2021). Here, removal of type-I small (Is) motor neurons (MNs) prompts functional rescue by type-I big (Ib) MNs (Wang et al. 2021). Despite these studies, mechanisms responsible for promoting cross-neuron plasticity between two non-contacting neurons are poorly understood.
In this preprint, Wang and colleagues provide evidence that in adjacent glia, Draper, an engulfment receptor required for endocytosis of cellular debris, and associated kinase Shark facilitate cross-neuron plasticity of Ib neurons. Importantly, the authors also report a behavioural impact of this plasticity. With glia identified as the third party responsible for transducing the cell death signal, a basis for studying molecular mechanisms underlying cross-neuron plasticity in an array of contexts is established by this study.
Key Findings
Engulfment receptor Draper is required for structural and functional cross-neuron plasticity
Given that engulfment-mediated signalling facilitates response to neuronal injury in bystander neurons (Hsu et al. 2021), the authors speculated that clearance of cellular debris may trigger a pathway that influences bystander neuron function. Therefore, to reveal the signalling mechanisms that facilitate cross-neuron plasticity of Ib MNs, the authors first considered the engulfment receptor Draper. Required for clearance of cellular debris following neurite injury and pruning, the authors confirmed that Draper is also needed following Is MN ablation due ectopic expression of cell death genes.
The involvement of Draper in cross-neuron plasticity was then examined. After Is ablation, the morphology and activity of co-innervating, bystander Ib motor neuron 4 (MN4-Ib) was assessed. Whereas MN4-Ib bouton number increased following Is ablation in a WT background, in a draper mutant (draperΔ5) background, no such change was observed (Fig. 1).
Figure 1. Draper is required for MN4-Ib structural cross-neuron plasticity. (A-D) MN4-Ib NMJs at L3 stage in control neurons with (A) and without (B) Is ablation, and in draperΔ5 background with (C) and without (D) Is ablation. (E) Quantification of MN4-Ib bouton number upon Is ablation in control and draperΔ5 backgrounds.
MN4-Ib functional plasticity was then analysed through spontaneous and induced electrophysiological recordings of muscle 4. Prior to Is ablation, MN4-Ib makes up 56% of the total excitatory postsynaptic potential (EPSP) of muscle 4 – considered the baseline level of MN4-Ib activity. Upon Is ablation, MN4-Ib activity is strongly increased, indicative of functional cross-neuron plasticity (Fig. 2). In a draperΔ5 background, however, this compensation is lost. The authors therefore confirmed that Draper is required for both structural and functional plasticity of MN4-Ib following Is ablation.
Draper signalling in glia facilitates cross-neuron plasticity
Despite this, the Draper-expressing cell type responsible for enacting this plasticity remained unknown. Considering Draper is expressed in muscle cells postsynaptically, and in the glia wrapping MN nerve bundles, Wang and colleagues performed cell-specific draper knockdowns and evaluated cross neuron-plasticity to investigate the cell type responsible. They show that glial cells were likely the major mediator of Ib MN cross-neuron plasticity, with muscle also capable, albeit to a lesser degree. This was further confirmed by showing that plasticity is possible even when Is and Ib neurons do not co-innervate the same muscle i.e. only glia wrapping the MN nerve bundle can be responsible for transducing the cell death signal.
Figure 2. Draper is required for MN4-Ib functional cross-neuron plasticity. (F) Ib EPSP and mEPSP traces upon Is ablation in control and draperΔ5 backgrounds. (I, J) Quantification of Ib EPSP amplitude normalised to Ib+Is combined amplitude (I), and quantal content normalised to Ib+Is combined quantal content (J) in control and draperΔ5 backgrounds upon Is ablation.
Probing signalling downstream of Draper, the kinase Shark was studied, which acts in conjunction with Draper to facilitate engulfment and promote transcription. shark knockdown proved consistent with the previous results for cell-specific draper knockdown, meaning signalling downstream of Draper in glia is needed for cross-neuron plasticity. Furthermore, overexpression of the draper-I isoform, and presumable elevation of downstream signalling, is sufficient to boost functional cross-neuron plasticity.
Functional cross-neuron plasticity is permissible at all larval stages
The authors then investigated the developmental window during which cross-neuron plasticity occurs, since neuronal plasticity tends to decline with age (Burke and Barnes 2006). The authors rendered Is ablation heat shock-inducible to facilitate temporal control. As such, at the desired developmental timepoint (late embryonic, 1st, 2nd, or 3rd instar larva), the animal could be exposed to heat shock and Is MNs acutely ablated. Significantly, structural plasticity was only achieved upon ablation in late embryonic stages, whereas functional plasticity was found following ablation in all larval stages (Fig. 3). This indicates that structural and functional plasticity may arise via different mechanisms, and that increased Ib activity is not solely a result of increased arbor size. Importantly, it implies modulation of synaptic active zone architecture.
Figure 3. Functional cross-neuron plasticity, but not structural, is permissible at all larval stages. (G) Quantification of MN4-Ib bouton number at L3 stage following controlled Is ablation at various stages in development. (F) Ib EPSP amplitude at L3 stage normalised to combined Ib+Is EPSP amplitude following controlled Is ablation at various stages in development.
Ib MN cross-neuron plasticity impinges on behavioural output
Lastly, the authors examined potential behavioural consequences of cross-neuron plasticity. Ib and Is MNs govern distinct larval movements: Ib MNs drive sustained actions e.g. foraging, crawling; Is MNs, on the other hand, fire transiently and enable quick behavioural responses e.g. escape via rolling. Accordingly, larvae with Is MNs ablated turned less, as this is an Is-governed action. These animals also showed elevated crawling speed, evidencing heightened Ib output due to cross-neuron plasticity. The ability to perform rolling responses was nevertheless lost, meaning that despite Ib functional compensation and subsequent affectation of Ib-governed responses, deficient Is circuitry and downstream behaviour could not be rescued.
Having started to unravel the underlying mechanism of cross-neuron plasticity, the next major question concerns the identity of the glia-to-neuron plasticity signal and the corresponding neuronal receptor. Additionally, given that some Ib MNs show greater predisposition to cross-neuron plasticity than others, it would also be interesting to determine the basis for this and whether plasticity can be forcibly induced in typically unreceptive neurons.
Significance of this work
Following axonal injury, Draper-mediated signalling in glia is known to mediate suppression of bystander neuron activity in the Drosophila wing (Hsu et al. 2021). Here, Wang and colleagues confirm that glia are the preeminent cell type in transducing the cell death signal to adjacent bystander neurons, influencing their structural and functional characteristics. The elucidation of the requirement of Draper-mediated signalling forms the foundation for further unpicking of the underlying mechanism, which has potential implications across the animal kingdom.
I chose this preprint because it adds to the existing repertoire of neuronal plasticity paradigms, while unlocking the door for future mechanistic avenues of research. I found it interesting that Ib MN plasticity is a non-cell autonomous mechanism, underlining again the importance of glial support.
Questions for the authors
- Although the risk of deleterious potentiation of an unrelated neuronal circuit might be greater, would cross-neuron plasticity also be possible in the CNS?
- Is cross-neuron plasticity triggered by cell death or rather by the presence of cellular debris?
- Might cross-neuron plasticity be triggered by pruning too? Could a similar mechanism apply to strengthening of the winning motor neuron in NMJ development following the retraction of losing competitors?
- You showed functional cross-neuron plasticity is possible throughout larval development. Is it possible in adults too?
References
Burke, Sara N., and Carol A. Barnes. 2006. “Neural Plasticity in the Ageing Brain.” Nature Reviews. Neuroscience 7 (1): 30–40.
Citri, Ami, and Robert C. Malenka. 2008. “Synaptic Plasticity: Multiple Forms, Functions, and Mechanisms.” Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 33 (1): 18–41.
Hoffman, H. 1950. “Local Re-Innervation in Partially Denervated Muscle; a Histophysiological Study.” The Australian Journal of Experimental Biology and Medical Science 28 (4): 383–97.
Hsu, Jiun-Min, Yunsik Kang, Megan M. Corty, Danielle Mathieson, Owen M. Peters, and Marc R. Freeman. 2021. “Injury-Induced Inhibition of Bystander Neurons Requires dSarm and Signaling from Glia.” Neuron 109 (3): 473–87.e5.
Magee, Jeffrey C., and Christine Grienberger. 2020. “Synaptic Plasticity Forms and Functions.” Annual Review of Neuroscience 43 (July): 95–117.
Modney, Barbara K., and Kenneth J. Muller. 1994. “Novel Synapses Compensate for a Neuron Ablated in Embryos.” Proceedings of the Royal Society of London. Series B, Containing Papers of a Biological Character. Royal Society 257 (September): 263–69.
Parnas, I., J. Dudel, I. Cohen, and C. Franke. 1984. “Strengthening of Synaptic Contacts of an Excitatory Axon on Elimination of a Second Excitatory Axon Innervating the Same Target.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 4 (7): 1912–23.
Wang, Yupu, Meike Lobb-Rabe, James Ashley, Veera Anand, and Robert A. Carrillo. 2021. “Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit.” The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 41 (7): 1401–17.
Posted on: 29 July 2023
doi: https://doi.org/10.1242/prelights.35201
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