Premium
Increased Sensitivity to Seizures in Mice Lacking Cellular Prion Protein
Author(s) -
Walz Roger,
Amaral Olavo B.,
Rockenbach Isabel C.,
Roesler Rafael,
Izquierdo Iván,
Cavalheiro Esper A.,
Martins Vilma R.,
Brentani Ricardo R.
Publication year - 1999
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1999.tb01583.x
Subject(s) - convulsant , kainic acid , pentylenetetrazol , epilepsy , status epilepticus , knockout mouse , kindling , pilocarpine , epileptogenesis , gene knockout , stimulation , seizure threshold , medicine , kindling model , pharmacology , endocrinology , biology , anticonvulsant , receptor , neuroscience , biochemistry , glutamate receptor , gene
Summary:Purpose: The physiologic role of the cellular prion protein (PrP c ) is unknown. Mice devoid of PrP c develop normally and show only minor deficits. However, electrophysiologic and histologic alterations found in these mice suggest a possible role for PrP c in seizure threshold and/or epilepsy. Methods: We tested the sensitivity of PrP c 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 c knockout group, in which 92.8% reached stage 5 or death after 4 days of stimulation, as opposed to 38.4% in wild‐type animals. After 10 injections, mortality 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 knockout mice, but only 33% among wild‐type animals. Pilocarpine‐induced SE (320 mg/kg) caused an 86.7% mortality in knockouts, as opposed to 40% in wild‐type animals. Finally, after kainic acid injections (10 mg/kg), 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 c ‐null mice, who at first analysis appeared to be completely normal. A possible role for PrP c in chronic and idiopathic (familial), secondary, or cryptogenic epilepsies in humans remains to be investigated.