Borna disease virus blocks potentiation of presynaptic activity through inhibition of protein kinase C signaling.
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.
Avenir group, INSERM, U563, Toulouse, France.
Romain
R
Volmer
Céline
C
Monnet
Daniel
D
Gonzalez-Dunia
D000818:Animals; D001890:Borna Disease / Q000503:physiopathology* / Q000821:virology*; D001891:Borna disease virus / Q000502:physiology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D008969:Molecular Sequence Data; D009474:Neurons / Q000502:physiology; D017729:Presynaptic Terminals / Q000502:physiology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology; D013572:Synaptic Vesicles / Q000502:physiology
D011493:Protein Kinase C