Pathogenesis of Herpes Simplex Virus Induced Experimental Seizures in Mice

• Main Authors: Hung-Ming Wu, 吳鴻明
• Other Authors: Kuei-Sen Hsu
• Format: Others
• Language: en_US
• Published: 2004
• Online Access: http://ndltd.ncl.edu.tw/handle/06673101609650436352

博士 === 國立成功大學 === 基礎醫學研究所 === 92 === 　　Epilepsy is well recognized as a sequel of viral encephalitis. Herpes simplex virus type 1 (HSV-1) is the most notorious pathogen in patients with acquired epilepsy after CNS viral infection. However, little is known about the pathogenesis of epilepsy after HSV-1 infection. Here, we developed a suitable mouse model of HSV encephalitis (HSVE) mimicking characteristics of HSVE in human to address the relationship of epilepsy and HSV-1 infections. The pathological lesions of mice inoculated with HSV-1 on the right corneal were widely distributed in frontotemporal regions, including piriform cortex, amygdale, hippocampus, brain stem, and other cortical regions correlated with the localization of viral antigens. Clinical observation found high incidence of reactive motor seizure behaviors correlated with ictal discharges usually originated from hippocampal regions at acute stage of HSVE in mice, which was confirmed by depth electrode recordings. In in vitro electrophysiological study, the surviving CA3 pyramidal cells in the hippocampal slices exhibited a more depolarizing resting membrane potential concomitant with an increase in membrane input resistance, and had a lower threshold to generate synchronized bursts as well as a significant decrease in the amplitude of afterhyperpolarization (AHP) than controls, which were persistent from acute infection till latent infection period. In addition, as the paired stimuli applied, synaptic transmission was easily evoked to epileptiform discharges in CA3 regions of the slices of infected mice. In in vivo study, it was found that the mice surviving from HSVE had increased short- and long-term seizure susceptibility to limbic convulsants (pentylenetetrazol and kainic acid) later in life compared with age-matched controls. Expectably, the surviving mice did display subclinical and recurrent seizure behaviors post inoculation. Extensive hippocampal electroencephalographic and behavioral monitoring demonstrated spontaneous seizures developed in 21 % and 41 % of infected mice by 120 and 210 days after inoculation, respectively; EEG seizures in another 21% and 17%, respectively. Immunocytochemical analyses revealed that most common initial brain lesions among surviving mice were located in piriform cortex, amygdale, and brain stem, and a few in CA3 subfield of hippocampus, but rare active neurodegeneration in these regions was noted during latently infected period. HSV-1 genomes were dominantly found in temporal regions and correlated to a high degree of subsequent seizure severity. Progressive mossy fiber sprouting in hippocampus and persistent astrocyte reactivation occurred in limbic structures of infected mice. As shown by Northern and Western blotting analyses, the expression of the transcripts and protein of the small-conductance Ca2+-activated potassium channel type 2 (SK2) gene were significantly less prominent in CA3 subfield during HSV-1 infection when compared with controls. Treatment of HSV-1-infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced a dose-dependent reduction on the signs of neurological deficits, pathological damages, and pentylenetetrazol-induced seizure severity. These results showed that HSV-1 infection in mice can lower seizure threshold to chemical convulsants and cause spontaneous limbic seizures later in life. The long-lasting neuronal depolarization, AHP dysfunction, and progressive synaptic reorganization in limbic regions may contribute to the basic processes of epileptogenesis of HSV-1 infection. Persistently latent viral genomes and reactive astrocytes in initial precipitating sites of HSVE may influence the microenvironment of brain tissues and enhance excitability of these neural tissues and loops. Taken together, they would facilitate the subsequent development of epilepsy. These findings may provide new therapeutic potentials for epilepsy associated with HSV-1infection.