Presynaptic contact and activity opposingly regulate postsynaptic dendrite outgrowth
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eLife assessment
This paper deploys elegant genetic tools to understand how synapses are formed in the Drosophila central nervous system. The synaptic connections between two identified neurons in the Drosophila central nervous system are used as a system to document the role of cell ablation and activity in dendrite growth and circuit wiring. In so doing, they identify a brief window of time that appears critical for these wiring and growth decisions.
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Abstract
The organization of neural circuits determines nervous system function. Variability can arise during neural circuit development (e.g. neurite morphology, axon/dendrite position). To ensure robust nervous system function, mechanisms must exist to accommodate variation in neurite positioning during circuit formation. Previously, we developed a model system in the Drosophila ventral nerve cord to conditionally induce positional variability of a proprioceptive sensory axon terminal, and used this model to show that when we altered the presynaptic position of the sensory neuron, its major postsynaptic interneuron partner modified its dendritic arbor to match the presynaptic contact, resulting in functional synaptic input (Sales et al., 2019). Here, we investigate the cellular mechanisms by which the interneuron dendrites detect and match variation in presynaptic partner location and input strength. We manipulate the presynaptic sensory neuron by (a) ablation; (b) silencing or activation; or (c) altering its location in the neuropil. From these experiments we conclude that there are two opposing mechanisms used to establish functional connectivity in the face of presynaptic variability: presynaptic contact stimulates dendrite outgrowth locally, whereas presynaptic activity inhibits postsynaptic dendrite outgrowth globally. These mechanisms are only active during an early larval critical period for structural plasticity. Collectively, our data provide new insights into dendrite development, identifying mechanisms that allow dendrites to flexibly respond to developmental variability in presynaptic location and input strength.
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eLife assessment
This paper deploys elegant genetic tools to understand how synapses are formed in the Drosophila central nervous system. The synaptic connections between two identified neurons in the Drosophila central nervous system are used as a system to document the role of cell ablation and activity in dendrite growth and circuit wiring. In so doing, they identify a brief window of time that appears critical for these wiring and growth decisions.
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Reviewer #1 (Public Review):
The manuscript by Heckman and Doe describes a nice set of experiments that extend previous studies of the plasticity in wiring and growth of a sensory axon terminal (Dbd) and its connection to a partner interneuron (A08a) in Drosophila embryonic/larval ventral nerve cord. The authors confirm and extend prior studies in the lab that showed misrouting of Dbd axons cause changes in its site of connection on medial versus lateral dendrites of A08a. The authors show using misrouting and ablation of Dbd that the site of axonal innervation plays a role in promoting dendrite outgrowth in that specific domain of the A08a dendritic field, suggesting a contact-dependent dendrite growth mechanism regulates early connections. The authors then describe a second mechanism where activity of the Dbd sensory neuron regulates …
Reviewer #1 (Public Review):
The manuscript by Heckman and Doe describes a nice set of experiments that extend previous studies of the plasticity in wiring and growth of a sensory axon terminal (Dbd) and its connection to a partner interneuron (A08a) in Drosophila embryonic/larval ventral nerve cord. The authors confirm and extend prior studies in the lab that showed misrouting of Dbd axons cause changes in its site of connection on medial versus lateral dendrites of A08a. The authors show using misrouting and ablation of Dbd that the site of axonal innervation plays a role in promoting dendrite outgrowth in that specific domain of the A08a dendritic field, suggesting a contact-dependent dendrite growth mechanism regulates early connections. The authors then describe a second mechanism where activity of the Dbd sensory neuron regulates a separate aspect of early connectivity, whereby reduced activity leads to increase A08a dendrite growth globally and increased activity suppresses overall A08a dendrite growth. This study fits with other work in the field on the role of activity in synaptic wiring while highlighting the opposing roles of contact versus activity in establishing early connection patterns. They also identify a brief developmental window where Dbd ablation causes A08a dendritic undergrowth, suggesting an early critical period for contact-dependent dendritic growth modulation, similar to that observed for activity-dependent plasticity. Overall, this is a nice study that provides important advances in our understanding of the plasticity of early neuronal wiring.
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Reviewer #2 (Public Review):
The authors report a series of genetic experiments that allow for the rigorous evaluation of the role of pre-synaptic contact and activity on dendrite morphogenesis and/or stabilization between a model pair of connected sensory and interneurons in the Drosophila larval CNS. Experiments to mis-position the presynaptic arbors of the DBD neuron reveal contact-dependent effects on post-synaptic dendrite growth. Ablation, silencing and activation experiments support the interesting model that neuronal activity in the sensory afferents act to globally constrain post-synaptic dendrite growth. Thus, coordination of presynaptic contact and activity act in opposition to sculpt post-synaptic dendrites. One weakness/limitation of the study is the inability of the authors to evaluate whether the observed effects are due …
Reviewer #2 (Public Review):
The authors report a series of genetic experiments that allow for the rigorous evaluation of the role of pre-synaptic contact and activity on dendrite morphogenesis and/or stabilization between a model pair of connected sensory and interneurons in the Drosophila larval CNS. Experiments to mis-position the presynaptic arbors of the DBD neuron reveal contact-dependent effects on post-synaptic dendrite growth. Ablation, silencing and activation experiments support the interesting model that neuronal activity in the sensory afferents act to globally constrain post-synaptic dendrite growth. Thus, coordination of presynaptic contact and activity act in opposition to sculpt post-synaptic dendrites. One weakness/limitation of the study is the inability of the authors to evaluate whether the observed effects are due to changes in the initiation of dendrite growth as opposed to maintenance or stabilization effects. The authors adequately acknowledge and discuss this limitation. Overall, this is a beautifully conducted study that adds new insights into synaptic partner matching.
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Reviewer #3 (Public Review):
In this manuscript, Emily Heckman and Chris Doe outline their investigation of how two specific partner neurons interact during the development of the Drosophila larval nerve cord, a specific proprioceptive sensory neuron (called 'dbd') and one of its postsynaptic partners (called 'A08a').
Experiments were executed that ask three questions:
1. How might dendrites of the A08a neuron postsynaptic to dbd change when this sensory neuron is silenced or over-activated?
2. How might those A08a dendrites change when the dbd presynaptic partner is experimentally removed?
3. Is there are critical period when dbd killing has maximal effect on changes to A08a dendrites?The aim was to reveal some of the cellular mechanisms that principally shape the development of postsynaptic dendrites during nervous system development.
Reviewer #3 (Public Review):
In this manuscript, Emily Heckman and Chris Doe outline their investigation of how two specific partner neurons interact during the development of the Drosophila larval nerve cord, a specific proprioceptive sensory neuron (called 'dbd') and one of its postsynaptic partners (called 'A08a').
Experiments were executed that ask three questions:
1. How might dendrites of the A08a neuron postsynaptic to dbd change when this sensory neuron is silenced or over-activated?
2. How might those A08a dendrites change when the dbd presynaptic partner is experimentally removed?
3. Is there are critical period when dbd killing has maximal effect on changes to A08a dendrites?The aim was to reveal some of the cellular mechanisms that principally shape the development of postsynaptic dendrites during nervous system development.
Overall, the paper is well written and the figures beautifully presented. However, I have reservations about the manuscript as it stands.
Foremost is the question as to what new insights this work reveals that have not already been clearly demonstrated by a number of other studies across a range of model systems, including those cited in the discussion? This work might distinguish itself at the level of detail achieved by precision made possible through the genetic tools available, yet it does not make use of other aspects, such as the connectome also available to probe more deeply into changes that the above manipulations provoke.The final experiment of inducing dbd cell killing at different stages of embryonic and larval development reveals what might be a critical period for cell contact-based regulation of postsynaptic dendritic growth regulation. This is a nice touch and could be the basis for interesting future work. However, much stronger would have been to have had a more robust sample size, clear demonstration of the dynamics of dbd cell killing itself (as potentially relevant to the A08a response) and, ideally, an independent verification via a separate method or on a different cell pair.
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