Circuit-specific proteome remodelling controls remote-memory recall

Abstract The mechanisms by which circuit-specific presynaptic molecular architectures in long-range pathways facilitate the transition from recent to remote memory remain unclear, even though this transition is central to systems-level consolidation and is relevant to both neuropsychiatric and neurodevelopmental disorders. In this study, we introduce an activity-dependent presynaptic BioID strategy, Active Neuron-specific Projection-eXclusive BioID (ActProX-ID), to define how recall activated presynaptic proteomes at the medial prefrontal cortex (mPFC)–basolateral amygdala (BLA) synapses are remodelled during both recent and remote fear recall. ActProX-ID uncovers presynaptic network reconfiguration between recall phases, identifies synaptic and trafficking modules that are differentially engaged as memories mature, and highlights disease-associated proteins whose orthologues exhibit conserved expression in the marmoset prefrontal cortex. Tetraspanin-7 (TSPAN7) is an activity-regulated protein that accumulates at remote recall-activated mPFC–BLA synapses and associates with complexin-2 (CPLX2) to facilitate SNARE-dependent vesicle recycling. Circuit-specific deletion of TSPAN7 or expression of the neurodevelopmental disease-linked TSPAN7 P172H variant disrupts remote contextual fear memory and socioemotional behaviour in mice. Here we show that recall-dependent presynaptic remodelling in the prefrontal–amygdala pathway supports the stabilisation of remote fear memory during system consolidation and implicate a TSPAN7–CPLX2 module in the socioemotional effects of human risk variants.