By Impairing Astrocyte Function, Virus May Cause Psychiatric Disorders

physiological malfunctions
By Karla Gale

NEW YORK (Reuters Health) Jul 07 - In transgenic mice that express the phosphoprotein
of Borna disease virus, glial cell dysfunction is accompanied by behavioral abnormalities
similar to those of human psychiatric disorders, Japanese scientists report.

"Recent epidemiological studies have suggested that people affected by mental diseases
show a high prevalence for antibodies to certain viruses, such as Borna disease virus,
herpes viruses and endogenous retrovirus," co-investigator Dr. Keizo Tomonaga told
Reuters Health. His group's findings support the hypothesis that viral infection may be
involved in the development of some psychiatric disorders.

In the Proceedings of the National Academy of Sciences, published online July 7th, Dr.
Tomonaga of Osaka University and colleagues note that Borna disease virus (BDV) is
highly neurotropic. In animal models, BDV infection is associated with behavioral
disturbances reminiscent of autism, schizophrenia and mood disorders.

"We wanted to see the specific effect of a viral protein on the neuronal function, as well as
to elucidate the molecular nature of Borna virus pathogenesis," Dr. Tomonaga explained.
To rule out the indirect effects of virus infection, such as inflammatory responses and
abnormalities in levels of cytokines, neurotrophic factors and neurotransmitters, the
researchers used an animal model of transgenic mice that expressed the phosphoprotein
(P) of BDV in the CNS.

"We focused on the P protein because we have previously found that this protein seems
to directly bind to a multifunctional host factor, amphoterin/HMGB1, which is a neurite
outgrowth factor expressed in the developing brains, and inhibits its functions in infected
cultured cell lines," Dr. Tomonaga added.

Different transgenic lines varied in the level of BDV P expressed. Thus, the authors could
observe a correlation between the expression of BDV (P) and the intensity of behavioral
and neurobiologic abnormalities.

They saw no evidence of reactive astrocytosis or neuronal cell death in the brains of the
animals, which "suggests that P can directly affect astrocyte function," they write.
However, synaptic density was reduced by about half by 8 months of age in the
high-expressor mice, indicating that "impairment of astrocytes' function in the transgenic
brains could be critical enough to cause deleterious effects in neuronal functions involved
in synaptic formation."

They also observed a reduction in brain-derived neurotropic factor and unbalanced
expression of serotonin receptors in transgenic brain tissue.

"We now think that the P protein can directly injure astrocyte functions, which could be
important for the maintenance of the central nervous system homeostasis, and neuronal
development as well," Dr. Tomonaga said. "So if there is a virus infection that can induce
astrocyte disabilities during the development of the brain and generate persistent
infection without inflammation, the virus may be able to cause behavioral disorders."

Proc Natl Acad Sci USA 2003.