Activity-dependent presynaptic proteomics reveals a prefrontal–amygdala release-site programme for remote contextual recall

Abstract

Remote memory retrieval engages distributed neuronal ensembles, yet how these ensembles organise long-range circuit output at the presynaptic molecular level remains poorly understood. Here, we develop Activity-dependent Projection-eXclusive BioID (ActProX-ID), an in vivo proximity-labelling strategy that combines TRAP2-dependent capture of behaviourally activated neurons with presynaptic membrane-targeted TurboID to profile projection-level, presynaptically enriched proteomic states. Application of ActProX-ID to the medial prefrontal cortex (mPFC)–basolateral amygdala (BLA) pathway during recent and remote fear-memory recall identified overlapping but phase-biased presynaptic programmes. Recent recall was associated with cytoskeletal and synaptic-organisation proteins, whereas remote recall preferentially engaged synaptic vesicle trafficking, transmembrane transport and release-site organisation. Subsequent analyses under remote contextual recall validated TSPAN7 as a remote recall-associated presynaptic component at mPFC–BLA terminals. TSPAN7 loss or expression of the disease-linked P172H variant impaired recall-associated synaptic remodelling, CPLX2 recruitment, SNAP25-positive release-site organisation and presynaptic release efficacy, and disrupted remote contextual fear memory while sparing recent contextual and tone-cued fear memory. These findings link behaviourally recruited prefrontal projection neurons to presynaptic molecular remodelling and reveal a TSPAN7–CPLX2-dependent release-site mechanism that controls remote contextual recall.

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