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The effects of herpes simplex virus infection on voltage-gated sodium currents in adult rat dorsal root ganglion neurones in vitro

Storey, Nina Margaret; (1999) The effects of herpes simplex virus infection on voltage-gated sodium currents in adult rat dorsal root ganglion neurones in vitro. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Herpes simplex virus (HSV) is a common human pathogen which attains a lifelong latent state in sensory ganglia after initial infection at the periphery. HSV is a potential viral vector for neurological diseases. HSV is known, however to affect the electrophysiological properties of excitable cells in vitro. This study investigated the mechanism of electrophysiological changes that occur during an HSV infection. Studies of adult rat dorsal root ganglion (DRG) neurones in the whole-cell voltage-damp mode showed that potassium and calcium voltage-gated currents were unaltered by wt HSV+ infection (wild type HSV Glasgow strain), whilst 70% of wt HSV 17+ infected DRG neurones had no sodium current after 24 hours. The tetrodotoxin sensitive and tetrodotoxin resistant sodium currents that remained in wt HSV 17+ infected DRG neurones after 24 hours were dramatically reduced in amplitude. The voltage dependence of these remaining sodium currents were unchanged. Experiments with the protein synthesis inhibitor, cycloheximide, revealed that viral entry into DRG neurones was not sufficient to cause a loss of sodium conductance, and that viral protein synthesis was necessary. Infection of DRG neurones with HSV mutants lacking functional regulatory immediate early genes ICP0, ICP4 and ICP27 showed that their expression is necessary for the loss of sodium conductance. Incubation of wt HSV 17+ infected DRG neurones with the viral DNA replication inhibitor, acyclovir, showed that viral DNA synthesis was necessary for the observed loss of sodium conductance. A possible mechanism of loss of sodium conductance in wt HSV 17+ infected DRG neurones is internalisation of sodium channels. The internalisation inhibitors, chloroquine, baflinomycin A1 and ammonium chloride prevented the loss of sodium conductance in wt HSV 17+ infected DRG neurones. A known trigger for internalisation of sodium channels from the surface of neurones is sodium influx. Treatment of DRG neurones with 50mM KCl and 0.1 mM veratridine, to evoke sodium entry, was sufficient to cause loss of sodium conductance. Preventing sodium entry during a wt HSV 17+ infection by incubating cells either in sodium free media or with tetrodotoxin, was sufficient to prevent the virally induced loss of sodium conductance.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The effects of herpes simplex virus infection on voltage-gated sodium currents in adult rat dorsal root ganglion neurones in vitro
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Herpes simpelx virus
URI: https://discovery.ucl.ac.uk/id/eprint/10105012
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