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Summary:Purpose: The physiologic role of the cellular prion protein (PrP') is unknown. Mice devoid of PrPC develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible role for PrP" in seizure threshold andor epilepsy.Methods: We tested the sensitivity of PrP" knockout mice to seizures induced by single convulsant or repeated subconvulsant (kindling) doses of pentylenetetrazol (PTZ), and to status epilepticus (SE) induced by kainic acid or pilocarpine.Results: In PTZ kindling, seizure severity progressed faster in the PrP' knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wildtype animals. After 10 injections, mortality was 85.7% among knockouts and 15.3% among controls. After a single PTZ injection (60 mgkg), overall mortality due to seizures was 91 % in knockout mice, but only 33% among wild-type animals. Pilocarpine-induced SE (320 mgkg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild-type animals. Finally, after kainic acid injections (10 mgkg), 70% of the knockouts developed at least one severe seizure, and 50% showed repetitive seizures, whereas no wild-type animal exhibited observable seizures.Conclusions: Animals lacking cellular prion protein expression are more susceptible to seizures induced by various convulsant agents. This is perhaps the most striking alteration yet found in PrP'-null mice, who at first analysis appeared to be completely normal. A possible role for PrP' in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans remains to be investigated. Key Words: PrionPrP"--Seizure-Epileps y-Kindling.Prions have long been known as the causative agents of spongiform encephalopathies, which can be transmitted through infection in livestock and humans but also by genetic inheritance in the latter (1). Their composition has been firmly established as consisting of a single protein termed scrapie prion protein (PrP'"). It has been shown that there are no differences between the amino acid sequences of PrP" and of its physiologic counterpart, cellular prion protein (PrP"). The only relevant difference between PrP"" and PrP" concerns their secondary structures, with the former displaying a much higher proportion of p-sheet conformational domains than the latter, which is mostly a-helical (2,3).The physiological function of PrP", however, remains unclear ( 1 4 ) . As it is located in the outer surface of cells, anchored by phosphatidylinositol glycolipid, it is a candidate for a signaling or, less likely, a transport function (3). Mice devoid of PrP" develop normally, showing normal learning (3,4), but have aberrant sleep patterns (3,5); moreover, one line of mice lacking PrP" developed cerebellar degeneration in old age (6). Mossy fiber alterations resembling those seen in temporal lobe epilepsy have recently been described in PrP" knockout mice (7). Moreover, one study has shown that y-aminobutyric acid type A (GABA,) rece...

Age, CT findings, Glasgow coma scale, pupil examination, and the presence of thoracic trauma at admission were independently associated with mortality at the time of discharge in Brazilian patients with severe TBI.