Glial activation precedes seizures and hippocampal neurodegeneration in measles virus-infected mice.
Intracerebral injection of hamster neurotropic (HNT) measles virus in weanling Balb/C mice leads to an encephalitis, which is characterized by glial activation, behavioral seizures, selective neurodegeneration, and, after approximately 7 days, death. To provide a better understanding of the underlying molecular pathology, we studied seizure evolution by continuously monitoring electroencephalographic (EEG) activity, examined neuroglia and neurons histologically, and measured the brain content of glia-derived neuroactive metabolites of the kynurenine pathway of tryptophan degradation. Microglia and astrocytes were activated as early as postinoculation day (PID) 1, with reactive microglia lining the extent of the alveus. This was followed by a more extensive microglial activation that specifically outlined hippocampal pyramidal neurons in areas CA1-CA3 and by increases in the hippocampal levels of the neurotoxins 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN). These changes preceded the onset of EEG seizures, which had a mean onset of 108 h after inoculation. Prominent hippocampal cell loss, demonstrated by Nissl- and silver staining, was apparent by PID 5. Thus, we speculate that early glial reactions to HNT inoculation result in the excess formation of 3-HK and QUIN, which in turn causes subclinical seizure activity, behavioral seizures, and, eventually, neurodegeneration. In addition to its conceptual implications, our study indicates that timely interventions modulating glial activation or 3-HK/QUIN synthesis may be of benefit in preventing or arresting seizure-induced neuronal damage.
Lehrmann
Elin
E
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21228, USA.
Guidetti
Paolo
P
Löve
Arthur
A
Williamson
John
J
Bertram
Edward H
EH
Schwarcz
Robert
R
D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D002452:Cell Count; D004396:Coloring Agents; D006224:Cricetinae; D004195:Disease Models, Animal; D004569:Electroencephalography / Q000706:statistics & numerical data; D018792:Encephalitis, Viral / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism / Q000502:physiology; D008459:Measles virus / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000473:pathology / Q000502:physiology; D008991:Monitoring, Physiologic; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D017966:Pyramidal Cells / Q000473:pathology / Q000502:physiology; D017378:Quinolinic Acid / Q000378:metabolism / Q000502:physiology; D012640:Seizures / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D014364:Tryptophan / Q000378:metabolism
D004396:Coloring Agents; C005045:3-hydroxykynurenine; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid