Adaptor Protein AP-3 Produces Synaptic Vesicles That Release at High Frequency by Recruiting Phospholipid Flippase ATP8A1

Overview

Journal Nat Neurosci

Date 2023 Sep 18

PMID 37723322

Authors

Hongfei Xu

Juan A Oses-Prieto

Mikhail Khvotchev

Shweta Jain

Jocelyn Liang

Alma Burlingame

Robert H Edwards

Affiliations

Soon will be listed here.

Abstract

Neural systems encode information in the frequency of action potentials, which is then decoded by synaptic transmission. However, the rapid, synchronous release of neurotransmitters depletes synaptic vesicles (SVs), limiting release at high firing rates. How then do synapses convey information about frequency? Here, we show in mouse hippocampal neurons and slices that the adaptor protein AP-3 makes a subset of SVs that respond specifically to high-frequency stimulation. Neurotransmitter transporters slot onto these SVs in different proportions, contributing to the distinct properties of release observed at different excitatory synapses. Proteomics reveals that AP-3 targets the phospholipid flippase ATP8A1 to SVs; loss of ATP8A1 recapitulates the defect in SV mobilization at high frequency observed with loss of AP-3. The mechanism involves recruitment of synapsin by the cytoplasmically oriented phosphatidylserine translocated by ATP8A1. Thus, ATP8A1 enables the subset of SVs made by AP-3 to release at high frequency.

Citing Articles

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