Experience-dependent glial pruning of synaptic glomeruli during the critical period

Abstract

Critical periods are temporally-restricted, early-life windows when sensory experience remodels synaptic connectivity to optimize environmental input. In the Drosophila juvenile brain, critical period experience drives synapse elimination, which is transiently reversible. Within olfactory sensory neuron (OSN) classes synapsing onto single projection neurons extending to brain learning/memory centers, we find glia mediate experience-dependent pruning of OSN synaptic glomeruli downstream of critical period odorant exposure. We find glial projections infiltrate brain neuropil in response to critical period experience, and use Draper (MEGF10) engulfment receptors to prune synaptic glomeruli. Downstream, we find antagonistic Basket (JNK) and Puckered (DUSP) signaling is required for the experience-dependent translocation of activated Basket into glial nuclei. Dependent on this signaling, we find critical period experience drives expression of the F-actin linking signaling scaffold Cheerio (FLNA), which is absolutely essential for the synaptic glomeruli pruning. We find Cheerio mediates experience-dependent regulation of the glial F-actin cytoskeleton for critical period remodeling. These results define a sequential pathway for experience-dependent brain synaptic glomeruli pruning in a strictly-defined critical period; input experience drives neuropil infiltration of glial projections, Draper/MEGF10 receptors activate a Basket/JNK signaling cascade for transcriptional activation, and Cheerio/FLNA induction regulates the glial actin cytoskeleton to mediate targeted synapse phagocytosis.

Developmental and age-related synapse elimination is mediated by glial Croquemort

“…Given that loss of Crq in glia blocks this decrease in synapse numbers early in adulthood, it appears that glial cells are responsible for promoting early loss of synapses in the adult brain. Consistent with our observations, dynamic changes in synapses have been observed during this time window in response to changes in sensory input 67–69 , and these have been shown to be regulated by the glial phagocytic receptor Drpr 70 .…”

Glia control experience-dependent plasticity in an olfactory critical period

“…Finally, recent work has found that astrocytic MEGF10 is also responsible for thalamo-cortical synapse engulfment in ocular dominance plasticity (Lee et al, 2022). Thus, Draper/MEGF10-mediated signaling orchestrates temporally limited critical period pruning in multiple experimental models (Lee et al, 2022;Nelson et al, 2024).…”

“…Ensheathing glia extend processes into VM7 to perform critical period pruning in a Draper-dependent manner Draper is a highly conserved engulfment receptor, and its genetic requirement for synapse removal during critical period plasticity suggested the straightforward hypothesis (Nelson et al, 2024) that it mediates phagocytosis of Or42a OSN terminals by ensheathing glia. Before directly testing this, we investigated if ensheathing glial processes infiltrate VM7 following critical period EB exposure, and if so, whether this morphological change is Draper-dependent.…”

“…Our odorant exposure protocol was adapted from the method of Golovin and colleagues (Golovin et al, 2019;Nelson et al, 2024). For critical period exposure (0 to 2 days post-eclosion), ten days after beginning crosses in standard bottles of fly food stoppered with cotton plugs, all adults (parents and any progeny that had eclosed) were anesthetized briefly with CO2 and discarded, and the cotton plugs were replaced with a layer of nylon mesh secured with rubber bands.…”