Presynaptic Nanoscale Components of Retrograde Synaptic Signaling

Barti, Benjámin and Dudok, Barna and Kenesei, Kata and Zöldi, Miklós and Miczán, Vivien and Balla, Gyula Y. and Zala, Diana and Tasso, Mariana and Sagheddu, Claudia and Kisfali, Máté and Tóth, Blanka and Ledri, Marco and Vizi E., Sylvester and Melis, Miriam and Barna, László and Lenkei, Zsolt and Soltész, Iván and Katona, István (2024) Presynaptic Nanoscale Components of Retrograde Synaptic Signaling. SCIENCE ADVANCES, 10 (22). No.-eado0077. ISSN 2375-2548

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Abstract

While our understanding of the nanoscale architecture of anterograde synaptic transmission is rapidly expanding, the qualitative and quantitative molecular principles underlying distinct mechanisms of retrograde synaptic communication remain elusive. We show that a particular form of tonic cannabinoid signaling is essential for setting target cell–dependent synaptic variability. It does not require the activity of the two major endocannabinoid-producing enzymes. Instead, by developing a workflow for physiological, anatomical, and molecular measurements at the same unitary synapse, we demonstrate that the nanoscale stoichiometric ratio of type 1 cannabinoid receptors (CB 1 Rs) to the release machinery is sufficient to predict synapse-specific release probability. Accordingly, selective decrease of extrasynaptic CB 1 Rs does not affect synaptic transmission, whereas in vivo exposure to the phytocannabinoid Δ 9 -tetrahydrocannabinol disrupts the intrasynaptic nanoscale stoichiometry and reduces synaptic variability. These findings imply that synapses leverage the nanoscale stoichiometry of presynaptic receptor coupling to the release machinery to establish synaptic strength in a target cell–dependent manner.

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