Activity-controlled proteolytic cleavage at the synapse

•Activity-controlled synaptic peptidases cleave proteins at, and in the vicinity of, synapses.•Each peptidase exhibits a set of proteolytic target proteins of its own.•Several peptidases cooperate to regulate distinct aspects of synaptic long-term potentiation.•Neurotrypsin may enhance synaptogenesis at activated synapses.

Activity-controlled enzymatic cleavage of proteins on the surface of synaptic membranes or in the synaptic or perisynaptic interstitial compartment represents a direct way to regulate synaptic structure, function, and number. Extracellular proteolysis at synapses was initially understood to be plasticity enabling by freeing synapses from the constraints provided by the extracellular matrix. However, recent observations indicate that at least part of the extracellular protein cleavage results in activation of previously cryptic functions that regulate adaptive changes of synapses and neuronal circuits. Here, we focus on peptidases with distinct localization and function at synapses combined with regulation by neuronal and synaptic activity, and evaluate their function in the context of developmental and/or adult synaptic plasticity.