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

Gutman-Wei, A. Y.; Sudarsanam, S.; Cabalinan, A. G.; Shahid, N.; Shi, A.; Guzman Clavel, L. E.; Spindler-Krage, S. M.; Agarwal, A.; Kolodkin, A. L.; Brown, S. P.

doi:10.1101/2025.08.08.669371

bioRxiv · 10.1101/2025.08.08.669371

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

Gutman-Wei, A. Y.·Sudarsanam, S.·Cabalinan, A. G.·Shahid, N.·Shi, A.·Guzman Clavel, L. E.·Spindler-Krage, S. M.·Agarwal, A.·Kolodkin, A. L.·Brown, S. P.

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Abstract

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.

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Gutman-Wei, A. Y., Sudarsanam, S., Cabalinan, A. G., Shahid, N., Shi, A., Guzman Clavel, L. E., Spindler-Krage, S. M., Agarwal, A., Kolodkin, A. L., Brown, S. P.. 2025-08-09. Cell-type-selective synaptogenesis during the development of excitatory connectivity in the mammalian neocortex. https://doi.org/10.1101/2025.08.08.669371

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