Borna Disease Virus Blocks Potentiation of Presynaptic Activity through Inhibition of Protein Kinase C Signaling

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Abstract
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. Here, we investigated whether BDV infection of neurons affected synaptic activity, by studying the rate of synaptic vesicle (SV) recycling, a good indicator of synaptic activity. Vesicular cycling was visualized in cultured hippocampal neurons synapses, using an assay based on the uptake of an antibody directed against the luminal domain of synaptotagmin I. BDV infection did not affect elementary presynaptic functioning, such as spontaneous or depolarization-induced vesicular cycling. In contrast, infection of neurons with BDV specifically blocked the enhancement of SV recycling that is observed in response to stimuli-induced synaptic potentiation, suggesting defects in long-term potentiation. Studies of signaling pathways involved in synaptic potentiation revealed that this blockade was due to a reduction of the phosphorylation by protein kinase C (PKC) of proteins that regulate SV recycling, such as myristoylated alanine-rich C kinase substrate (MARCKS) and Munc18–1/nSec1. Moreover, BDV interference with PKC-dependent phosphorylation was identified downstream of PKC activation. We also provide evidence suggesting that the BDV phosphoprotein interferes with PKC-dependent phosphorylation. Altogether, our results reveal a new mechanism by which a virus can cause synaptic dysfunction and contribute to neurobehavioral disorders. The central nervous system is the target of many persistent viral infections that can induce diverse pathological manifestations. Besides causing meningitis or encephalitis, viruses can infect neurons without overt structural damage, but nevertheless alter cellular functioning by yet-undefined molecular mechanisms, thereby disturbing homeostasis and causing disease. Here, the authors have studied the infection by Borna disease virus, an RNA virus that persists in the brain of a wide variety of animals and causes behavioral disturbances. Using primary cultures of neurons, they show that Borna disease virus interferes specifically with the activity-dependent enhancement of synaptic activity, one form of synaptic plasticity that is believed to be essential for memory formation. This interference was correlated to a reduced phosphorylation of neuronal targets by protein kinase C (PKC), a kinase that plays important roles in the regulation of neuronal activity. The authors also provide evidence that the viral phosphoprotein may be responsible for this interference, possibly by competing with the phosphorylation of endogenous cellular PKC substrates. These results illustrate an intriguing aspect of viral interference with neuronal function and reveal a new mechanism whereby a virus can cause synaptic dysfunction and contribute to neurobehavioral disorders.