Shahid, N. | bioRxiv Science

bioRxiv2025

Cell-type-selective synaptogenesis during the development of excitatory connectivity in the mammalian neocortex

The function of mammalian neocortex relies on the timing of axon extension and establishment of cell-type-biased patterns of excitatory synaptic connections. A subtype of excitatory neurons, layer 6 corticothalamic neurons (L6CThNs), ultimately exhibit a marked preference for synapsing onto parvalbumin-positive (PV) inhibitory interneurons over more common excitatory cells in layers 6 and 4 (L6, L4). We show that the intracortical axons of L6CThNs develop in phases, elongating within L6, then pausing before extending translaminar branches into L4. Decreasing L6CThN excitability selectively enhanced axon growth in L6 but not later elaboration in L4. For both layers, we tested whether preferential synaptogenesis onto rarer PV interneurons, or promiscuous synapse formation followed by selective pruning, generated adult connectivity. We found that L6CThNs formed functional AMPA-receptor-containing synapses preferentially onto PV interneurons. Silent L6CThN synapses were not detected. Our findings show that cell-type-biased synaptogenesis underlies the formation of functional cell-type-specific excitatory connections in the neocortex.

neuroscience↗

bioRxiv2025

Mef2c Controls Postnatal Callosal Axon Targeting by Regulating Sensitivity to Ephrin Repulsion

Cortical connectivity is contingent on ordered emergence of neuron subtypes followed by the formation of subtype-specific axon projections. Intracortical circuits, including long-range callosal projections, are crucial for information processing, but mechanisms of intracortical axon targeting are still unclear. We find that the transcription factor Myocyte enhancer factor 2-c (Mef2c) directs the development of somatosensory cortical (S1) layer 4 and 5 pyramidal neurons during embryogenesis. During early postnatal development, Mef2c expression shifts to layer 2/3 callosal projection neurons (L2/3 CPNs), and we find a novel function for Mef2c in targeting homotopic contralateral cortical regions by S1-L2/3 CPNs. We demonstrate, using functional manipulation of EphA-EphrinA signaling in Mef2c-mutant CPNs, that Mef2c downregulates EphA6 to desensitize S1-L2/3 CPN axons to EphrinA5-repulsion at their contralateral targets. Our work uncovers dual roles for Mef2c in cortical development: regulation of laminar subtype specification during embryogenesis, and axon targeting in postnatal callosal neurons. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/634300v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@108c788org.highwire.dtl.DTLVardef@163c6c3org.highwire.dtl.DTLVardef@18e6d8borg.highwire.dtl.DTLVardef@1b9f9e4_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIMef2c is required for the development of L4 and L5 neurons in the embryonic neocortex C_LIO_LIPostnatally, Mef2c is enriched in L2/3 neurons and is required for axon targeting C_LIO_LIL2/3-specific Mef2c deletion leads to EphA6 upregulation C_LIO_LIMef2c deletion in L2/3 neurons sensitizes them to EfnA5 repulsion in the contralateral cortex C_LI

neuroscience↗

bioRxiv2023

Agricultural pesticides do not suppress infection of Biomphalaria (Gastropoda) by Schistosoma mansoni (Trematoda)

BackgroundSchistosomiasis is a neglected tropical disease caused by trematodes of the genus Schistosoma. The pathogen is transmitted via freshwater snails. These snails indirectly benefit from agricultural pesticides which affect their enemy species. Pesticide exposure of surface waters may thus increase the risk of schistosomiasis transmission unless it also affects the pathogen. MethodologyWe tested the tolerance of the free-swimming infective life stages (miracidia and cercariae) of Schistosoma mansoni to the commonly applied insecticides diazinon and imidacloprid. Additionally, we investigated whether these pesticides decrease the ability of miracidia to infect and further develop as sporocysts within the host snail Biomphalaria pfeifferi. Principal findingsExposure to imidacloprid for 6 and 12 hours immobilized 50% of miracidia at 150 and 16 g/L, respectively (nominal EC50); 50% of cercariae were immobilized at 403 and 284 g/L. Diazinon immobilized 50% of miracidia at 51 and 21 g/L after 6 and 12 hours; 50% of cercariae were immobilized at 25 and 13 g/L. This insecticide tolerance is lower than those of the host snail B. pfeifferi but comparable to those of other commonly tested freshwater invertebrates. Exposure for up to 6 hours decreased the infectivity of miracidia at high sublethal concentrations (48.8 g imidacloprid/L and 10.5 g diazinon/L, i.e. 20 - 33 % of EC50) but not at lower concentrations commonly observed in the field (4.88 g imidacloprid/L and 1.05 g diazinon/L). The development of sporocysts within the snail host was not affected at any of these test concentrations. ConclusionsInsecticides did not affect the performance of S. mansoni at environmentally relevant concentrations. Accordingly, pesticide exposure is likely to increase the risk of schistosomiasis transmission by increasing host snail abundance without affecting the pathogen. Our results illustrate how the ecological side effects of pesticides are linked to human health, emphasizing the need for appropriate mitigation measures. Author summarySchistosomiasis is a major public health problem in 51 countries worldwide. Transmission requires human contact with freshwater snails that act as intermediate hosts, releasing free-swimming life stages of the trematodes. The host snails are highly tolerant to agricultural pesticides used in plant protection products. Pesticides enter freshwaters via drift and runoff, and indirectly foster the spread of host snails via adverse effects on more sensitive competitor and predator species in the water. Increasing the abundance of intermediate hosts raises potential contact with the human definitive host while transmission of the pathogen is not affected. Here we show that pesticides do not affect the ability of the trematode Schistosoma mansoni to infect and develop within its host snail Biomphalaria pfeifferi at environmentally relevant concentrations. Consequently, risk of schistosomiasis increases when pesticide pollution favours the proliferation of snail hosts whilst not negatively affecting the free-living parasites nor their development in their snail hosts. Measures to mitigate pesticide pollution of freshwaters should be a concern in public health programs to sustainably roll back schistosomiasis. Intersectional collaborations are required to bridge the gap between the agricultural and the public health sector in search of sustainable and safe methods of crop production.

systems biology↗