Regulation of GABAA and Glutamate Receptor Expression, Synaptic Facilitation and Long-Term Potentiation in the Hippocampus of Prion Mutant Mice

Abstract

BackgroundPrionopathies are characterized by spongiform brain degeneration, myoclonia, dementia, and periodic electroencephalographic (EEG) disturbances. The hallmark of prioniopathies is the presence of an abnormal conformational isoform (PrPsc) of the natural cellular prion protein (PrPc) encoded by the Prnp gene. Although several roles have been attributed to PrPc, its putative functions in neuronal excitability are unknown. Although early studies of the behavior of Prnp knockout mice described minor changes, later studies report altered behavior. To date, most functional PrPc studies on synaptic plasticity have been performed in vitro. To our knowledge, only one electrophysiological study has been performed in vivo in anesthetized mice, by Curtis and coworkers. They reported no significant differences in paired-pulse facilitation or LTP in the CA1 region after Schaffer collateral/commissural pathway stimulation.Methodology/Principal FindingsHere we explore the role of PrPc expression in neurotransmission and neural excitability using wild-type, Prnp −/− and PrPc-overexpressing mice (Tg20 strain). By correlating histopathology with electrophysiology in living behaving mice, we demonstrate that both Prnp −/− mice but, more relevantly Tg20 mice show increased susceptibility to KA, leading to significant cell death in the hippocampus. This finding correlates with enhanced synaptic facilitation in paired-pulse experiments and hippocampal LTP in living behaving mutant mice. Gene expression profiling using Illumina™ microarrays and Ingenuity pathways analysis showed that 129 genes involved in canonical pathways such as Ubiquitination or Neurotransmission were co-regulated in Prnp −/− and Tg20 mice. Lastly, RT-qPCR of neurotransmission-related genes indicated that subunits of GABAA and AMPA-kainate receptors are co-regulated in both Prnp −/− and Tg20 mice.Conclusions/SignificancePresent results demonstrate that PrPc is necessary for the proper homeostatic functioning of hippocampal circuits, because of its relationships with GABAA and AMPA-Kainate neurotransmission. New PrPc functions have recently been described, which point to PrPc as a target for putative therapies in Alzheimer's disease. However, our results indicate that a “gain of function” strategy in Alzheimer's disease, or a “loss of function” in prionopathies, may impair PrPc function, with devastating effects. In conclusion, we believe that present data should be taken into account in the development of future therapies.

Role of PrPC Expression in Tau Protein Levels and Phosphorylation in Alzheimer’s Disease Evolution

“…This reinforces previously reported microarray data in N2a cells [65] and PrP C mutant mice at younger stages compared with adults (2-3 months) [72][73][74]. However, these observations are partially in contrast with some recently published results, using human neuroblastoma [75] and HEK293 cells [74].…”

Prion Protein Modulates Monoaminergic Systems and Depressive-like Behavior in Mice

“…Evidence has been reported of co-regulation of expression of the Prnp gene with both glutamate and ␥-aminobutyric acid receptors (22), but protein content was not included in that study. Notably, whereas the content of both 5HT5A and TH were increased in PrP C -null tissue when compared with wild-type, no difference was detected for 5HT1A, D1 receptor, the SERT transporter, nor the TPH enzyme, all of which pertain to the same neurochemical pathways.…”

“…Functional consequences of the direct binding of PrP C to several neurotransmitter receptors were reported (18 -21), and neurotransmission may be further affected by PrP C through co-regulation of the expression of neurotransmitter receptor subunits (22). In particular, antibody-mediated engagement of PrP C reduced signaling through adenylyl cyclase, phospholipases C and A 2 , from at least three subtypes of the G proteincoupled serotonin (5HT) receptor and modulated the crosstalk among these pathways in a cell line that expresses 5HT receptors as well as PrP C (23,24).…”

Inhibition of IL-1β Signaling Normalizes NMDA-Dependent Neurotransmission and Reduces Seizure Susceptibility in a Mouse Model of Creutzfeldt–Jakob Disease

“…Genetic PrP C depletion results in increased hippocampal NMDAR-mediated excitation and 92 glutamate exicitotoxicity (Khosravani et al, 2008). In addition, PrP knockout (KO) mice are reported to be 93 more susceptible to seizures induced by kainic acid (KA) than wild-type (WT) controls (Walz et al, 1999; 94 Rangel et al, 2007), perhaps because of facilitated NMDAR-mediated excitation in the hippocampus (Maglio 95 et al, 2004;Rangel et al, 2009); although this issue remains controversial (Striebel et al, 2013b;Carulla et 96 al., 2015).…”

“…There is evidence 285 that interleukin-1 (IL-1 ) promotes Src family kinase (SFK)-mediated Tyr1472 phosphorylation of GluN2B 286 (Viviani et al, 2003), and its brain levels are high in CJD (Sharief et al, 1999;Shi et al, 2013;Llorens et al, …”