Enhanced susceptibility of Prnp‐deficient mice to kainate‐induced seizures, neuronal apoptosis, and death: Role of AMPA/kainate receptors

Abstract

Normal physiologic functions of the cellular prion protein (PrPc) are still elusive. This GPI-anchored protein exerts many functions, including roles in neuron proliferation, neuroprotection or redox homeostasis. There are, however, conflicting data concerning its role in synaptic transmission. Although several studies report that PrPc participates in NMDA-mediated neurotransmission, parallel studies describe normal behavior of PrPc-mutant mice. Abnormal axon connections have been described in the dentate gyrus of the hippocampi of PrPc-deficient mice similar to those observed in epilepsy. A study indicates increased susceptibility to kainate (KA) in these mutant mice. We extend the observation of these studies by means of several histologic and biochemical analyses of KA-treated mice. PrPc-deficient mice showed increased sensitivity to KA-induced seizures in vivo and in vitro in organotypic slices. In addition, we show that this sensitivity is cell-specific because interference experiments to abolish PrPc expression increased susceptibility to KA in PrPc-expressing cells. We indicate a correlation of susceptibility to KA in cells lacking PrPc with the differential expression of GluR6 and GluR7 KA receptor subunits using real-time RT-PCR methods. These results indicate that PrPc exerts a neuroprotective role against KA-induced neurotoxicity, probably by regulating the expression of KA receptor subunits.

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).…”

“…Lastly, pioneering electrophysiological studies (using PrP c knockout slices) by Collinge established that PrP c participates in long-term potentiation (Collinge et al, 1994;Curtis et al, 2003;Maglio et al, 2006). More recently, it has been shown that the absence of PrP c alters the expression of several neurotransmitter receptors (see (Maglio et al, 2004;Rangel et al, 2007) for examples). Thus, Prnp 0/0 mice show increased neuronal excitability as well as enhanced glutamate excitotoxicity by modulation of NMDA as well as kainate receptors (Khosravani et al, 2008b).…”

Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrP C -deficiency

“…Prnp 0/0 mice have a normal development and are completely resistant to prion infections (5) and, although useful in the study of disease pathogenesis, have heightened curiosity as to PrP C 's function. Reported phenotypes in Prnp 0/0 mice are disparate and sometimes subtle: these include altered circadian rhythms (6,7), sensitivity to oxidative stress (8), excitability of hippocampal neurons (9,10), sensitivity to seizure (11,12), age-related behavioral deficits (13)(14)(15), deficits in olfaction (16), and altered maintenance of the peripheral nervous system (17). The nonlethal effect of PrP C -deficiency has provoked interest in the concept of functional degeneracy, with a hypothetical PrP functional homolog being deduced from genetic data and termed "π" (18,19).…”

Prion Neurotoxicity: Insights from Prion Protein Mutants

“…Moreover, after ischemic or traumatic brain injury, lesion size is larger in Prn-p 0/0 compared to wild-type mice (Hoshino et al, 2003;McLennan et al, 2004;Sakurai-Yamashita et al, 2005;Spudich et al, 2005). Finally, Prn-p 0/0 mice are more susceptible to kainate-induced seizures (Rangel et al, 2007) and their retinal photoreceptors are more prone to light-induced degeneration (Frigg et al, 2006).…”