Glia control experience-dependent plasticity in an olfactory critical period

Reviewer #1 (Public Review):

Time periods in which experience regulates early plasticity in sensory circuits are well established, but the mechanisms that control these critical periods are poorly understood. In this manuscript, Leier and Foden and colleagues examine early-life critical periods that regulate the Drosophila antennal lobe, a model sensory circuit for understanding synaptic organization. Using early-life (0-2 days old) exposure to distinct odorants, they show that constant odor exposure markedly reduces the volume, synapse number, and function of the VM7 glomerulus. The authors offer evidence that these changes are mediated by invasion of ensheathing glia into the glomerulus where they phagocytose connections via a mechanism involving the engulfment receptor Draper.

This manuscript is a striking example of a study where the questions are interesting, the authors spent a considerable amount of time to clearly think out the best experiments to ask their questions in the most straightforward way, and expressed the results in a careful, cogent, and well-written fashion. It was a genuine delight to read this paper. I have two experimental suggestions that would really round out existing work to better support the existing conclusions and some instances where additional data or tempered language in describing results would better support their conclusions. Overall, though, this is an incredibly important finding, a careful analysis, and an excellent mechanistic advance in understanding sensory critical period biology.

Reviewer #2 (Public Review):

Sensory experiences during developmental critical periods have long-lasting impacts on neural circuit function and behavior. However, the underlying molecular and cellular mechanisms that drive these enduring changes are not fully understood. In Drosophila, the antennal lobe is composed of synapses between olfactory sensory neurons (OSNs) and projection neurons (PNs), arranged into distinct glomeruli. Many of these glomeruli show structural plasticity in response to early-life odor exposure, reflecting the sensitivity of the olfactory circuitry to early sensory experiences.

In their study, the authors explored the role of glia in the development of the antennal lobe in young adult flies, proposing that glial cells might also play a role in experience-dependent plasticity. They identified a critical period during which both structural and functional plasticity of OSN-PN synapses occur within the ethyl butyrate (EB)-responsive VM7 glomerulus. When flies were exposed to EB within the first two days post-eclosion, significant reductions in glomerular volume, presynaptic terminal numbers, and postsynaptic activity were observed. The study further highlights the importance of the highly conserved engulfment receptor Draper in facilitating this critical period plasticity. The authors demonstrated that, in response to EB exposure during this developmental window, ensheathing glia increase Draper expression, infiltrate the VM7 glomerulus, and actively phagocytose OSN presynaptic terminals. This synapse pruning has lasting effects on circuit function, leading to persistent decreases in both OSN-PN synapse numbers and spontaneous PN activity as analyzed by perforated patch-clamp electrophysiology to record spontaneous activity from PNs postsynaptic to Or42a OSNs.

In my view, this is an intriguing and potentially valuable set of data. However, since I am not an expert in critical periods or habituation, I do not feel entirely qualified to assess the full significance or the novelty of their findings, particularly in relation to existing research.