Persistent, noncytolytic infection of neurons by Borna disease virus interferes with ERK 1/2 signaling and abrogates BDNF-induced synaptogenesis.
Infection of the central nervous system by Borna disease virus (BDV) provides a unique model to study the mechanisms whereby a persistent viral infection can impair neuronal function and cause behavioral diseases reminiscent of mood disorders, schizophrenia, or autism in humans. In the present work, we studied the effect of BDV infection on the response of hippocampal neurons, the main target for this virus, to the neurotrophin BDNF. We showed that persistent infection did not affect neuronal survival or morphology. However, it blocked BDNF-induced ERK 1/2 phosphorylation, despite normal expression of the TrkB BDNF receptor. In addition, BDNF-induced expression of synaptic vesicle proteins was abrogated, which resulted in severely impaired synaptogenesis and defects in synaptic organization. Thus, we provide the first evidence that a virus can interfere specifically with neurotrophin-regulated neuroplasticity, thereby hampering proper neuronal connectivity. These results may help to understand the behavioral disorders associated with BDV infection.
Hans
Aymeric
A
Unité des Virus Lents, CNRS URA 1930, Institut Pasteur, Paris, France.
Bajramovic
Jeffrey J
JJ
Syan
Sylvie
S
Perret
Emmanuelle
E
Dunia
Irene
I
Brahic
Michel
M
Gonzalez-Dunia
Daniel
D
D000818:Animals; D001891:Borna disease virus / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure / Q000821:virology; D003588:Cytopathogenic Effect, Viral; D006624:Hippocampus / Q000166:cytology / Q000821:virology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D001523:Mental Disorders / Q000821:virology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009473:Neuronal Plasticity; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000648:ultrastructure / Q000821:virology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D013569:Synapses / Q000648:ultrastructure*
D019208:Brain-Derived Neurotrophic Factor; D009419:Nerve Tissue Proteins; D020813:Receptor, trkB; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases