Glial expression of Borna disease virus phosphoprotein induces behavioral and neurological abnormalities in transgenic mice

Abstract

One hypothesis for the etiology of behavioral disorders is that infection by a virus induces neuronal cell dysfunctions resulting in a wide range of behavioral abnormalities. However, a direct linkage between viral infections and neurobehavioral disturbances associated with human psychiatric disorders has not been identified. Here, we show that transgenic mice expressing the phosphoprotein (P) of Borna disease virus (BDV) in glial cells develop behavioral abnormalities, such as enhanced intermale aggressiveness, hyperactivity, and spatial reference memory deficit. We demonstrate that the transgenic brains exhibit a significant reduction in brain-derived neurotrophic factor and serotonin receptor expression, as well as a marked decrease in synaptic density. These results demonstrate that glial expression of BDV P leads to behavioral and neurobiological disturbances resembling those in BDVinfected animals. Furthermore, the lack of reactive astrocytosis and neuronal degeneration in the brains indicates that P can directly induce glial cell dysfunction and also suggests that the transgenic mice may exhibit neuropathological and neurophysiological abnormalities resembling those of psychiatric patients. Our results provide a new insight to explore the relationship between viral infections and neurobehavioral disorders. N eurobehavioral disorder is a complex disease that must arise from the actions of many genes and͞or environmental factors. A number of working hypotheses propose that viral infection, as an environmental factor, contributes to the induction of neuropathological and neurophysiological disturbances, resulting in a wide range of behavioral abnormalities (1-3). Studies using animal models reveal that viruses can induce neurobehavioral disturbances predominantly through an indirect pathway that involves the release of various factors by infiltrating cells or by glial cells (3-5). This process seems to be a common pathway to neuronal injury in a wide variety of neurodegenerative disorders in which glial proliferation typically accompanies. In the case of major psychiatric disorders, however, a spectrum of neurological abnormalities associated with glial cell dysfunction is found in brains without neuronal degeneration (2, 6-8). Despite increased insight into the mechanisms of the neuropathogenesis of different viruses, viral infections or specific antigens that develop neurobehavioral abnormalities associated with psychiatric disorders have not yet been identified.Borna disease virus (BDV) is a highly neurotropic virus that belongs to the Mononegavirales. Natural infection of BDV has now been found in a wide variety of vertebrates, suggesting that the host range of this virus probably includes all warm-blooded animals (9, 10). BDV persistently infects the CNS of many animal species and causes behavioral disturbances, such as anxiety, aggression, hyperactivity, abnormal play behavior, and cognitive deficits, reminiscent of autism, schizophrenia, and mood disorders (11)(12)(13)(14). Thus, studies on this virus...

Comprehensive analysis of endogenous bornavirus-like elements in eukaryote genomes

“…However, because P was identified as a BDV pathogenic factor, expression of integrated P may have adverse effects on host animals. In fact, transgenic mice expressing BDV N protein do not show any sign of neuronal disease, whereas abnormal behaviour has been observed in BDV P transgenic mice [6,7,66]. Therefore, integration and expression of a P-like protein might have an adverse effect, producing a survival disadvantage for a host animal.…”

“…N encapisidates the viral RNA to form the viral nucleocapsid. P is a cofactor of viral polymerase L and is also a phosphorylation decoy involved in BDV pathogenicity [6][7][8][9][10][11][12][13]. Viral gene products N, P and L are the minimal components of viral ribonucleoprotein (vRNP) [14].…”

Borna Disease Virus Infects Human Neural Progenitor Cells and Impairs Neurogenesis

“…Other cellular types, however, such as astrocytes (4) and neural progenitor cells (37,38), have been shown to be infected and might be involved in BDVinduced neuropathogenesis. Indeed, astrocyte dysfunction can play a key role in the pathogenesis of CNS disorders (9), and striking neurobehavioral abnormalities have been reported in mice expressing BDV phosphoprotein (BDV-P) selectively in glial cells (20). The alteration of progenitor cells and neurogenesis also would critically affect brain function.…”

Transgenic Mice Expressing the Nucleoprotein of Borna Disease Virus in either Neurons or Astrocytes: Decreased Susceptibility to Homotypic Infection and Disease

“…Very recently, a study analyzing transgenic mice expressing the P of BDV under the control of a GFAP promoter also did not detect any gross neuroanatomical alterations such as neuronal loss or astrogliosis (27). Interestingly, however, detailed analysis of brains from BDV-P-transgenic mice revealed some neurobiological abnormalities, including reduced synaptic density and lower expression of brain-derived neurotrophic factor and serotonin receptor (27). At present, we cannot rule out the possibility that subtle changes in brain cytoarchitecture or behavior might also have occurred in our N-transgenic animals.…”

“…Negative effects of BDV replication in the CNS of mice lacking a fully competent immune system were only detectable in very sensitive learning tests (38). Very recently, a study analyzing transgenic mice expressing the P of BDV under the control of a GFAP promoter also did not detect any gross neuroanatomical alterations such as neuronal loss or astrogliosis (27). Interestingly, however, detailed analysis of brains from BDV-P-transgenic mice revealed some neurobiological abnormalities, including reduced synaptic density and lower expression of brain-derived neurotrophic factor and serotonin receptor (27).…”