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.
Aberrations in glutamatergic neurotransmission has been implicated in some seizure models, and we have recently reported that reduced cortical AMPA receptor (AMPAR) expression (predominantly GluA4- containing AMPARs) in parvalbumin-containing (PV<sup>+</sup>) inhibitory interneurons, could underlie seizure generation in the stargazer mutant mouse.
To test this, we used a pentylenetetrazole- (PTZ-) kindling model mouse to investigate changes to hippocampal parvalbumin- (PV-) positive neurons, extracellular matrix molecules, and perineuronal nets (PNNs) after the last kindled seizure.
Those data demonstrated that pharmaco-genetic seizure attenuation through targeting parvalbumin neurons rather than pyramidal neurons may be a novel and relatively safe approach for treating refractory TLE.
Previous research has shown that in vivo on-demand optogenetic stimulation of inhibitory interneurons expressing parvalbumin (PV) is sufficient to suppress seizures in a mouse model of temporal lobe epilepsy (TLE).
Furthermore, PV neurons are highly vulnerable to status epilepticus (SE, prolonged seizure activity), although the underlining mechanism remains to be clarified.
Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons.