Increased Sensitivity to Seizures in Mice Lacking Cellular Prion Protein

Abstract

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...

Neuron-Specific mRNA Complexity Responses during Hippocampal Apoptosis after Traumatic Brain Injury

“…Current evidence suggests that the mechanism underlying the neuroprotective properties of PrP c involves a copper-binding activity that protects cells from oxidative damage (Brown et al, 1997a(Brown et al, , 2002. In support of this hypothesis, cerebellar cell cultures from PrP c null mice are more susceptible to oxidative stress than wild-type mice (Brown et al, 1997b), and PrP c null mice are more susceptible to acute seizures and kindling induced by different protocols than their wild-type counterparts (Walz et al, 1999). Such a neuroprotective function may indicate a possible reason why we observed PrP c to be highly upregulated in the dentate gyrus after TBI in this study.…”

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…In addition, both lines showed deficits in synaptic transmission (Collinge et al, 1994;Herms et al, 1995) and increased sensitivity to oxidative stress (Brown et al, 2002). Recent studies indicate that these mice also show increased susceptibility to glutamate excitotoxicity (Khosravani et al, 2008a;Rangel et al, 2007;Walz et al, 1999;Walz et al, 2002) as a result of changes in the expression of glutamate receptor subunits (Khosravani et al, 2008a;Lledo et al, 1996;Rangel et al, 2007). More recently, a conditional knockout of PrP c has been generated (Mallucci et al, 2002).…”

Absence of the Cellular Prion Protein Exacerbates and Prolongs Neuroinflammation in Experimental Autoimmune Encephalomyelitis

“…For example, deletion of PrP C increased neuronal predisposition to damage by modulating susceptibility to apoptosis 9,10 and the negative consequences of oxidative stress. [11][12][13] Furthermore, in vivo studies demonstrated that PrP C -deficient mice were more prone to seizure induction, 14 and exhibited an increased extent of cerebral damage following an ischemic challenge. 15 In contrast, adenovirus-mediated PrP C overexpression reduced CNS damage in a rat model of cerebral ischemia.…”