Neuronal activity modulates the incorporation of newly translated PSD-95 into a robust structure as revealed by STED and MINFLUX

Guerth, C.-M.; do Rego Barros Fernandes Lima, M. A.; Macarron Palacios, V.; Hubrich, J.; Cereceda Delgado, A. R.; Mougios, N.; Opazo, F.; D'Este, E.

doi:10.1101/2023.10.18.562700

bioRxiv · 10.1101/2023.10.18.562700

Neuronal activity modulates the incorporation of newly translated PSD-95 into a robust structure as revealed by STED and MINFLUX

Guerth, C.-M.·do Rego Barros Fernandes Lima, M. A.·Macarron Palacios, V.·Hubrich, J.·Cereceda Delgado, A. R.·Mougios, N.·Opazo, F.·D'Este, E.

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Abstract

The postsynaptic density component PSD-95 undergoes activity-dependent plasticity mechanisms that rely on protein synthesis and structural remodeling. How synaptic activity can influence these dynamics at the single synapse level remains unclear. Here we combine genome-editing, pulse-chase experiments, STED and 3D MINFLUX nanoscopy on hippocampal neuronal cultures to study the integration of newly translated PSD-95 molecules at postsynaptic sites and their rearrangement within individual clusters at near-molecular resolution. We show that the amount of newly translated PSD-95 recruited to individual synapses scales with synaptic size, and modulates in a bidirectional manner, resulting in less new protein following excitatory and more new protein following inhibitory stimulation. Furthermore, we show that within synaptic clusters PSD-95 has a dispersed organization that is largely robust to long-lasting changes in activity. Altogether, this work sheds new light on the mechanisms underlying plasticity at the single synapse level, adding previously inaccessible information.

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Guerth, C.-M., do Rego Barros Fernandes Lima, M. A., Macarron Palacios, V., Hubrich, J., Cereceda Delgado, A. R., Mougios, N., Opazo, F., D'Este, E.. 2023-10-20. Neuronal activity modulates the incorporation of newly translated PSD-95 into a robust structure as revealed by STED and MINFLUX. https://doi.org/10.1101/2023.10.18.562700

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