Deficiency of urokinase-type plasminogen activator and its receptor affects social behavior and increases seizure susceptibility.

Extracellular proteolysis initiated by the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) regulates the development of inhibitory neuronal circuits in the cerebral cortex and tissue remodeling after epileptogenic brain injury. To study the function of different components of the uPA-uPAR system on behavior and epileptogenesis, and to complement our previous studies on naïve and injured mice deficient in the uPA-encoding gene Plau or the uPAR-encoding gene Plaur, we analyzed the behavioral phenotype, seizure susceptibility, and perineuronal nets surrounding parvalbumin-positive inhibitory interneurons in Plau and Plaur (double knockout dKO) mice. In a climbing test, dKO mice showed reduced interest towards the environment as compared with Wt mice (p < 0.01). In a social approach test, however, dKO mice spent more time than Wt mice exploring the compartment containing a stranger mouse than the empty compartment (p < 0.05). Moreover, in a social interaction test, dKO mice exhibited increased contact time (p < 0.01). Compared with Wt mice, the dKO mice also had a longer single contact duration (p < 0.001) with the stranger mouse. In the elevated plus-maze, grooming, and marble burying tests, the anxiety level of dKO mice did not differ from that of Wt mice. Rearing time in an exploratory activity test, and spatial learning and memory in the Morris swim navigation task were also comparable between dKO and Wt mice. In the pentylenetetrazol (PTZ) seizure-susceptibility test, dKO mice had a shorter latency to the first epileptiform spike (p = 0.0001) and a greater total number of spikes (p < 0.001) than Wt mice. The dKO genotype did not affect the number of cortical perineuronal nets. Our findings indicate that Plau/Plaur-deficiency leads to a more social phenotype toward other mice with diminished interest in the surrounding environment, and increased seizure susceptibility.