Adult cortical neurons can produce tissue‐type plasminogen activator (tPA), an extracellular protease that plays a critical role in fibrinolysis and tissue remodelling processes. There is growing evidence that extracellular proteolysis may be involved in synaptic plasticity, axonal remodelling and neurotoxicity in the adult central nervous system. Here we show that transgenic mice overexpressing tPA in post‐natal neurons have increased and prolonged hippocampal long‐term potentiation (LTP), and improved performance in spatial orientation learning tasks. Extracellular proteolysis catalysed by tPA may facilitate synaptic micro‐remodelling, and thereby play a role in activity‐dependent neuronal plasticity and learning.