Seizure, neuron loss, and mossy fiber sprouting in herpes simplex virus type 1-infected organotypic hippocampal cultures

Epilepsia. 2004 Apr;45(4):322-32. doi: 10.1111/j.0013-9580.2004.37403.x.


Purpose: Epileptic seizures are frequently seen after viral encephalitis. Herpes simplex virus type 1 (HSV-1) encephalitis is the most common cause of acquired epilepsy in humans. However, little information is available about the neuropathogenesis of HSV-1-associated seizures. We have developed an in vitro HSV-1-infected organotypic hippocampal slice culture to elucidate the underlying mechanisms of HSV-1-associated acute seizure activity.

Methods: Hippocampal slice cultures were prepared from postnatal day 10 to 12 rat pups. Wild-type HSV-1 strain RE (1 x 10(5) PFU) was applied to cultures at 14 days in vitro. The excitability of CA3 pyramidal cells and hippocampal network properties were measured with electrophysiological recordings. Hematoxylin-eosin (H&E) and Timm stains were used.

Results: HSV-1 infection induces epileptiform activity, neuron loss, and subsequently a dramatic increase of mossy fiber sprouting in the supragranular area. With intracellular recordings, surviving CA3 pyramidal cells exhibited a more depolarizing resting membrane potential concomitant with an increase in membrane input resistance and had a lower threshold to generate synchronized bursts and a decrease in the amplitude of afterhyperpolarization than did controls. When the antiherpes agent acyclovir was applied with a delay of 1 or 24 h after HSV-1 infection, a dramatic inhibition of HSV-1 replication and protection of the neuron loss were observed.

Conclusions: These results suggest that a direct change in the excitability of the hippocampal CA3 neuronal network and HSV-1-induced neuron loss resulting in subsequent mossy fiber reorganization may play an important role in the generation of epileptiform activity.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Cell Death*
  • Herpes Simplex / pathology
  • Herpes Simplex / physiopathology*
  • Herpes Simplex / virology
  • Herpesvirus 1, Human* / isolation & purification
  • Male
  • Mossy Fibers, Hippocampal / pathology
  • Mossy Fibers, Hippocampal / virology*
  • Neurons / pathology*
  • Neurons / virology*
  • Organ Culture Techniques
  • Rats
  • Rats, Sprague-Dawley
  • Seizures / pathology*
  • Seizures / physiopathology
  • Seizures / virology*