Increased sensitivity to seizures in mice lacking cellular prion protein

Roger Walz, Olavo B. Amaral, Isabel C. Rockenbach, Rafael Roesler, Iván Izquierdo, Esper A. Cavalheiro, Vilma R. Martins, Ricardo R. Brentani

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

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 wildtype 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.

Original languageEnglish (US)
Pages (from-to)1679-1682
Number of pages4
JournalEpilepsia
Volume40
Issue number12
DOIs
StatePublished - Jan 1 1999

Fingerprint

Seizures
Pentylenetetrazole
Wild Animals
Convulsants
Epilepsy
Pilocarpine
Status Epilepticus
Kainic Acid
Knockout Mice
Injections
Mortality
Prion Proteins

Keywords

  • Epilepsy
  • Kindling
  • PrP(c)
  • Prion
  • Seizure

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Walz, R., Amaral, O. B., Rockenbach, I. C., Roesler, R., Izquierdo, I., Cavalheiro, E. A., ... Brentani, R. R. (1999). Increased sensitivity to seizures in mice lacking cellular prion protein. Epilepsia, 40(12), 1679-1682. https://doi.org/10.1111/j.1528-1157.1999.tb01583.x

Increased sensitivity to seizures in mice lacking cellular prion protein. / Walz, Roger; Amaral, Olavo B.; Rockenbach, Isabel C.; Roesler, Rafael; Izquierdo, Iván; Cavalheiro, Esper A.; Martins, Vilma R.; Brentani, Ricardo R.

In: Epilepsia, Vol. 40, No. 12, 01.01.1999, p. 1679-1682.

Research output: Contribution to journalArticle

Walz, R, Amaral, OB, Rockenbach, IC, Roesler, R, Izquierdo, I, Cavalheiro, EA, Martins, VR & Brentani, RR 1999, 'Increased sensitivity to seizures in mice lacking cellular prion protein', Epilepsia, vol. 40, no. 12, pp. 1679-1682. https://doi.org/10.1111/j.1528-1157.1999.tb01583.x
Walz R, Amaral OB, Rockenbach IC, Roesler R, Izquierdo I, Cavalheiro EA et al. Increased sensitivity to seizures in mice lacking cellular prion protein. Epilepsia. 1999 Jan 1;40(12):1679-1682. https://doi.org/10.1111/j.1528-1157.1999.tb01583.x
Walz, Roger ; Amaral, Olavo B. ; Rockenbach, Isabel C. ; Roesler, Rafael ; Izquierdo, Iván ; Cavalheiro, Esper A. ; Martins, Vilma R. ; Brentani, Ricardo R. / Increased sensitivity to seizures in mice lacking cellular prion protein. In: Epilepsia. 1999 ; Vol. 40, No. 12. pp. 1679-1682.
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abstract = "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 wildtype 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.",
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AU - Walz, Roger

AU - Amaral, Olavo B.

AU - Rockenbach, Isabel C.

AU - Roesler, Rafael

AU - Izquierdo, Iván

AU - Cavalheiro, Esper A.

AU - Martins, Vilma R.

AU - Brentani, Ricardo R.

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N2 - 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 wildtype 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.

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