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Borna disease virus phosphoprotein interferes with neuronal function and contributes to neurobehavioral disorders

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Infection by Borna disease virus (BDV) enables the study of the molecular mechanisms whereby a virus can persist in the central nervous system and lead to altered brain function, in the absence of overt cytolysis and inflammation. This neurotropic virus infects a wide variety of vertebrates and causes behavioral diseases. The basis of BDV-induced behavioral impairment remains largely unknown.

Previously, we have shown that BDV specifically blocks the activity-dependent enhancement of synaptic activity, both by studying the recycling of synaptic vesicles and by using electrophysiological approaches on BDV-infected neuronal networks grown on microelectrode arrays. This suggested defects in long-term potentiation, one key component of learning at the cellular level. Studies of signaling pathways involved in synaptic potentiation revealed that this blockade was due to an interference with PKC-dependent signaling in neurons, likely due to the viral phosphoprotein (P).

Here, we used recombinant BDV with mutated PKC phosphorylation sites on P [1], and showed that this mutation restored the phosphorylation of PKC substrates in neurons after stimulation. Moreover, using primary neuronal cultures grown on micro-electrode arrays (MEA), we provide evidence that the activity-dependent enhancement of synaptic activity was restored when cultures were infected with the P-mutated virus. Therefore, preventing P protein phosphorylation by PKC completely restores normal neuronal activity upon stimulation in infected neurons.

Together, these findings illustrate a novel mechanism whereby a viral protein can cause synaptic dysfunction and contribute to neurobehavioral disorders.

References

  1. 1.

    Schmid S, Mayer D, Schneider U, Schwemmle M: Functional characterization of the major and minor phosphorylation sites of the P protein of Borna disease virus. J Virol. 2007, 81: 5497-5507. 10.1128/JVI.02233-06.

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Correspondence to Daniel Gonzalez-Dunia.

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Prat, C., Schmid, S., Schwemmle, M. et al. Borna disease virus phosphoprotein interferes with neuronal function and contributes to neurobehavioral disorders. BMC Proc 2, P56 (2008) doi:10.1186/1753-6561-2-s1-p56

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Keywords

  • Synaptic Activity
  • Microelectrode Array
  • Primary Neuronal Culture
  • Synaptic Potentiation
  • Infected Neuron