A unifying mechanism for presynaptic homeostatic plasticity at mammalian peripheral and central synapses.

Presynaptic homeostatic plasticity (PHP) is a potent form of adaptive plasticity that has been documented at synapses as diverse as the glutamatergic Drosophila neuromuscular junction (NMJ), cholinergic mammalian NMJ (including human), and glutamatergic synapses in the mammalian brain. We define secreted class III semaphorin as a unifying, trans-synaptic signal necessary for PHP at highly divergent synapses. Sema3a drives the rapid induction of PHP at the cholinergic mouse NMJ and synapses in the adult hippocampus (CA1), including cross-modal potentiation of inhibitory transmission. Three-dimensional electron microscopy (EM) reveals Sema3a-dependent active zone expansion, presynaptic stabilization, and the maintenance of synapse organization during PHP. Mechanistically, Sema3a promotes vesicle redistribution from a non-releasing to recycling and readily releasable vesicle pool. Finally, presynaptic-signal transduction is also commonly deployed, requiring activation of PlexinA4 and an integrin beta-1 (ITGB1) co-receptor. The widespread utilization of common PHP mechanisms emphasizes the translational potential of model organisms toward promoting neuronal resilience to combat brain disorders and disease.