Protein tyrosine phosphatase receptor type Z (Ptprz, also known as PTPzeta or RPTPbeta) is preferentially expressed in the CNS as a major chondroitin sulfate proteoglycan (CSPG). Ptprz interacts with the PSD95 family through its intracellular carboxyl-terminal PDZ-binding motif in the postsynaptic density. Ptprz-deficient adult mice display impairments in spatial and contextual learning. Here, we identified the proteolytic processing of Ptprz by plasmin in the mouse brain, which is markedly enhanced after kainic acid (KA)-induced seizures. We mapped plasmin cleavage sites in the extracellular region of Ptprz by cell-based assays and in vitro digestion experiments with recombinant proteins. These findings indicate that Ptprz is a physiological target for activity-dependent proteolytic processing by the tPA/plasmin system, and suggest that the proteolytic cleavage is involved in the functional processes of the synapses during learning and memory.