Herpes Simplex Virus type 1 (HSV-1) increases the excitability of rat neocortical neurons and triggers amyloid precursor protein (APP) processing.

Introduction: HSV-1 infection may spread within the central nervous system and cause neurological disorders including encephalitis and epileptic seizures. Recurrent HSV-1 infections have also been proposed to play a co-factorial role in the pathogenesis of Alzheimer’s disease. Objective: Aim of our study was to determine the effects of HSV-1 on electrophysiological properties of cortical neurons, and the pathophysiological impact of virally induced changes. Methods: Patch-clamp, immunofluorescence and Western blot experiments were performed on rat cultured cortical neurons either soon after challenge with HSV-1 or 12 24 hours post-infection (hpi). Results: Cell exposure to HSV-1 induced membrane depolarization (11.8±0.7 mV) that triggered action potentials and increased the discharge rate of spontaneously firing neurons (from 0.1±0.1 to 1.1±0.3 Hz). This effect depended on viral binding to neuronal membrane. In fact, when cells were challenged with HSV-1 pretreated with heparin (which prevents the binding of viral glicoproteins to membrane receptors) no depolarization was observed whereas when we applied UV-inactivated HSV-1 (that binds to membrane but is unable to replicate) the observed responses were similar to those produced by active virus. In most neurons, membrane depolarization started soon after HSV-1 application and steady-state was reached after 2 10 s. This effect was due to both inhibition of leak K+ currents and increase of persistent Na+ currents (+53% at 20 mV). Neither transient Na+ currents nor Ca2+ currents were affected. Similar effects were observed 12 hpi. The HSV-1-induced neuronal hyperexcitability triggered intracellular Ca2+ signals promoting APP processing and intracellular and extracellular accumulation of amyloid-b peptide and several neurotoxic APP fragments. Conclusions: Changes in neuronal electrophysiological properties induced by HSV-1 may play a role in the pathophysiology of epileptic seizures and neurodegeneration