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

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.