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1.
Neuroscience ; 160(4): 731-43, 2009 Jun 02.
Article in English | MEDLINE | ID: mdl-19285121

ABSTRACT

The hypothesis of an early vulnerability of the serotonergic system to prion infection was investigated in a murine model of bovine spongiform encephalopathy (BSE). Behavioral tests targeted to 5-HT functions were performed in the course of infection to evaluate circadian activity, anxiety-like behavior, pain sensitivity and the 5-HT syndrome. The first behavioral change was a decrease in nocturnal activity detected at 30% of incubation time. Further behavioral alterations including nocturnal hyperactivity, reduced anxiety, hyperalgesia and exaggerated 5-HT syndrome were observed at 60%-70% of incubation time, before the onset of clinical signs. The same tests performed in 5-HT-depleted mice and in prion protein-deficient mice revealed behavioral abnormalities similar in many aspects to those of BSE-infected mice. Histological and biochemical analysis showed alterations of the serotonergic system in BSE-infected and prion protein-deficient mice. These results indicate that BSE infection affects the homeostasis of serotonergic neurons and suggest that the disruption of prion protein normal function contributes to the early pathological changes in our mouse model of BSE. A similar process may occur in the human variant Creutzfeldt-Jacob disease, as suggested by the early symptoms of alterations in mood, sleep and pain sensitivity.


Subject(s)
Brain/metabolism , Encephalopathy, Bovine Spongiform/metabolism , Mental Disorders/metabolism , PrPC Proteins/deficiency , PrPSc Proteins/toxicity , Serotonin/metabolism , Animals , Anxiety Disorders/genetics , Anxiety Disorders/metabolism , Anxiety Disorders/physiopathology , Brain/physiopathology , Brain Stem/cytology , Brain Stem/metabolism , Brain Stem/physiopathology , Cattle , Chronobiology Disorders/genetics , Chronobiology Disorders/metabolism , Chronobiology Disorders/physiopathology , Disease Models, Animal , Disease Progression , Encephalopathy, Bovine Spongiform/physiopathology , Female , Homeostasis/physiology , Mental Disorders/genetics , Mental Disorders/physiopathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/cytology , Neurons/metabolism , Pain/genetics , Pain/metabolism , Pain/physiopathology , PrPC Proteins/genetics , PrPSc Proteins/metabolism , Raphe Nuclei/cytology , Raphe Nuclei/metabolism , Raphe Nuclei/physiopathology , Serotonin Syndrome/genetics , Serotonin Syndrome/metabolism , Serotonin Syndrome/physiopathology , Time Factors
2.
Eur J Neurosci ; 21(9): 2311-9, 2005 May.
Article in English | MEDLINE | ID: mdl-15932590

ABSTRACT

Prion diseases are neurodegenerative pathologies characterized by apoptotic neuronal death. Although the late execution phase of neuronal apoptosis is beginning to be characterized, the sequence of events occurring during the early decision phase is not yet well known. In murine cortical neurons in primary culture, apoptosis was first induced by exposure to a synthetic peptide homologous to residues 106-126 of the human prion protein (PrP), PrP106-126. Exposure to its aggregated form induced a massive neuronal death within 24 h. Apoptosis was characterized by nuclear fragmentation, neuritic retraction and fragmentation and activation of caspase-3. During the early decision phase, reactive oxygen species were detected after 3 h. Using immunocytochemistry, we showed a peak of phosphorylated c-Jun-N-terminal kinase (JNK) translocation into the nucleus after 8 h, along with the activation of the nuclear c-Jun transcription factor. Both pharmacological inhibition of JNK by SP600125 and overexpression of a dominant negative form of c-Jun significantly reduced neuronal death, while the MAPK p38 inhibitor SB203580 had no effect. Apoptosis was also studied after exposure of tg338 cortical neurons in primary culture to sheep scrapie agent. In this model, prion-induced neuronal apoptosis gradually increased with time and induced a 40% cell death after 2 weeks exposure. Immunocytochemical analysis showed early c-Jun activation after 7 days. In summary, the JNK-c-Jun pathway plays an important role in neuronal apoptosis induced by PrP106-126. This pathway is also activated during scrapie infection and may be involved in prion-induced neuronal death. Pharmacological blockade of early pathways opens new therapeutic prospects for scrapie PrP-based pathologies.


Subject(s)
Apoptosis/physiology , JNK Mitogen-Activated Protein Kinases/metabolism , Neurons/metabolism , Peptide Fragments/pharmacology , Prions/pharmacology , Scrapie/metabolism , Scrapie/pathology , Animals , Cell Nucleus/metabolism , Cerebral Cortex/pathology , Female , Mice , Mice, Mutant Strains , Neurons/pathology , Phosphorylation , Pregnancy , Proto-Oncogene Proteins c-jun/metabolism , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects , Signal Transduction/physiology , p38 Mitogen-Activated Protein Kinases/metabolism
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