Increased sensitivity to seizures in mice lacking cellular prion protein

Purpose: The physiologic role of the cellular prion protein (PrPc) is unkno wn. Mice devoid of PrPc develop normally and show only minor deficits. Howe ver, electrophysiologic and histologic alterations found in these mice sugg est a possible:role fur PrPc in seizure threshold and/or epilepsy. Methods: We tested the sensitivity of PrPc knockout mice to seizures induce d by single convulsant or repeated subconvulsant (kindling) doses of pentyl enetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine. Results. In PTZ kindling, seizure severity progressed faster in the PrPc kn ockout group, in which 92.8% reached stage 5 or death after 4 days of stimu lation, as opposed to 38.4% in wildtype animals: After 10 injections, morta lity was 85.7% among knockouts and 15.3% among controls. After a single PTZ injection (60 mg/kg), overall mortality due to seizures was 91% in knockou t mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 m g/kg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild-typ e animals. Finally, after kainic acid injections (10 mg/kg), 70% of the kno ckouts developed at least one severe seizure, and 50% showed repetitive sei zures, whereas no wild-type animal exhibited observable seizures. Conclusions: Animals lacking cellular prion protein expression are more sus ceptible to seizures induced by various convulsant agents. This is perhaps the most striking alteration yet found in PrPc-null mice, who at first anal ysis appeared to be completely normal. A possible role for PrPc in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans r emains to be investigated.