Alterations in neurotrophin and neurotrophin receptor gene expression patterns in the rat central nervous system following perinatal Borna disease virus infection

Zocher, M.; Czub, Stefanie; Schulte‐Mönting, Jürgen; Jc, de la Torre; Sauder, Christian

doi:10.3109/13550280009091947

Cited by 54 publications

(41 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Damage of DGCs could, alternatively, originate from interference of BDV with proper synaptic functions that may ultimately lead to axonal deterioration, synaptic disconnection from target neurons, and finally death of the DGCs. This view is compatible with recent data indicating that BDV can indeed disturb synaptic plasticity by blocking BDNF-induced signaling events that regulate neuronal growth and also synaptic transmission (13,39).…”

Section: Vol 79 2005 Bdv-induced Neuronal Damage Of Granule Cells 1supporting

confidence: 81%

Borna Disease Virus Replication in Organotypic Hippocampal Slice Cultures from Rats Results in Selective Damage of Dentate Granule Cells

Mayer

Fischer

Schneider

et al. 2005

J Virol

View full text Add to dashboard Cite

In the hippocampus of Borna disease virus (BDV)-infected newborn rats, dentate granule cells undergo progressive cell death. BDV is noncytolytic, and the pathogenesis of this neurodevelopmental damage in the absence of immunopathology remains unclear. A suitable model system to study early events of the pathology is lacking. We show here that organotypic hippocampal slice cultures from newborn rat pups are a suitable ex vivo model to examine BDV neuropathogenesis. After challenging hippocampal slice cultures with BDV, we observed a progressive loss of calbindin-positive granule cells 21 to 28 days postinfection. This loss was accompanied by reduced numbers of mossy fiber boutons when compared to mock-infected cultures. Similarly, the density of dentate granule cell axons, the mossy fiber axons, appeared to be substantially reduced. In contrast, hilar mossy cells and pyramidal neurons survived, although BDV was detectable in these cells. Despite infection of dentate granule cells 2 weeks postinfection, the axonal projections of these cells and the synaptic connectivity patterns were comparable to those in mock-infected cultures, suggesting that BDVinduced damage of granule cells is a postmaturation event that starts after mossy fiber synapses are formed. In summary, we find that BDV infection of rat organotypic hippocampal slice cultures results in selective neuronal damage similar to that observed with infected newborn rats and is therefore a suitable model to study BDV-induced pathology in the hippocampus.Borna disease virus (BDV) is a nonsegmented negativestrand RNA virus that persistently infects the central nervous system (CNS) and causes behavioral abnormalities in a broad range of vertebrates (17,25). Depending on the age and immune status of the host, BDV infection may present as immune-mediated neurological disease with fatal outcome (Borna disease) or subtle behavioral alterations without overt inflammation (17,25). BDV infection is potentially linked to psychiatric diseases, as BDV-specific antibodies were identified in sera of psychiatric patients with higher prevalence than in sera from control cohorts (24). However, attempts to confirm human BDV by nonserological methods, including detection of viral nucleic acid by nested reverse transcription-PCR or virus isolation, revealed inconsistent results (35); this issue is therefore still controversial.Rats are the best-characterized animal models for studying BDV-induced pathogenesis. Depending on the age of the rat at the time of infection, the spectrum of BDV-caused diseases ranges from a progressive immune-mediated meningoencephalitis to behavioral abnormalities (17,25,26). In adult immunocompetent rats, BDV infection causes a biphasic disease characterized by a classical immune-mediated CNS disorder. This disease is associated with massive neuronal destruction and behavioral disturbances, the near-resolution of inflammatory infiltrates, virus persistence, and signs of chronic neurological disease. In contrast to infected adult rats, infection of neon...

show abstract

Section: Vol 79 2005 Bdv-induced Neuronal Damage Of Granule Cells 1supporting

confidence: 81%

Borna Disease Virus Replication in Organotypic Hippocampal Slice Cultures from Rats Results in Selective Damage of Dentate Granule Cells

Mayer

Fischer

Schneider

et al. 2005

J Virol

View full text Add to dashboard Cite

show abstract

“…In addition, neonatally BDV-infected rats show learning and memory deficits, as well as hyperactivity, in the absence of an inflammatory response (34,35). In neonatally infected rats, an abnormal level in BDNF and 5-HT receptors was also demonstrated (36,37). These similarities between BDV-infected animals and P transgenic mice may indicate that P is a main contributor to BDV-induced neuronal abnormalities.…”

Section: Discussionmentioning

confidence: 68%

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

Kamitani

Ono

Yoshino

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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...

show abstract

“…In neonatally infected rats, BDV causes a life-long persistent infection of the CNS with minimal signs of classical inflammatory cell infiltration (e.g., encephalitis and meningitis) and the absence of overt clinical disease. Nonetheless, neonatal BDV infection is associated with a progressive loss of granule cells in the dentate gyrus of the hippocampus, Purkinje cells in the cerebellum, and GABA-ergic neurons in the neocortex (5,16,18,45).Because BDV establishes a persistent noncytolytic infection in various cell lines and primary neurons and astrocytes in vitro (6,20,34), the mechanisms of neuronal degeneration in vivo remain unclear. Previous studies have indicated that even if the virus does not infect microglia in vivo, neonatal BDV infection is associated with strong microgliosis (6, 22, 38).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Ovanesov

Sauder

Rubin

et al. 2006

J Virol

View full text Add to dashboard Cite

Neonatal Borna disease virus (BDV) infection of the rat brain is associated with microglial activation and damage to the certain neuronal populations. Since persistent BDV infection of neurons in vitro is noncytolytic and noncytopathic, activated microglia have been suggested to be responsible for neuronal cell death in vivo. However, the mechanisms of activation of microglia in neonatally BDV-infected rat brain have not been investigated. To address these issues, activation of primary rat microglial cells was studied following exposure to purified BDV or to persistently BDV-infected primary cortical neurons or after BDV infection of primary mixed neuron-glial cultures. Neither purified virus nor BDV-infected neurons alone activated primary microglia as assessed by the changes in cell shape or production of the proinflammatory cytokines. In contrast, in the BDV-infected primary mixed cultures, we observed proliferation of microglia cells that acquired the round morphology and expressed major histocompatibility complex molecules of classes I and II. These manifestations of microglia activation were observed in the absence of direct BDV infection of microglia or overt neuronal toxicity. In addition, compared to uninfected mixed cultures, activation of microglia in BDV-infected mixed cultures was associated with a significantly greater lipopolysaccharide-induced release of tumor necrosis factor alpha, interleukin 1␤, and interleukin 10. Taken together, the present data are the first in vitro evidence that persistent BDV infection of neurons and astrocytes rather than direct exposure to the virus or dying neurons is critical for activating microglia.Borna disease virus (BDV) is a nonsegmented, negativestrand RNA virus that persistently infects the central nervous system (CNS) and causes behavioral abnormalities in a broad spectrum of warm-blooded animals (3,12,22). In neonatally infected rats, BDV causes a life-long persistent infection of the CNS with minimal signs of classical inflammatory cell infiltration (e.g., encephalitis and meningitis) and the absence of overt clinical disease. Nonetheless, neonatal BDV infection is associated with a progressive loss of granule cells in the dentate gyrus of the hippocampus, Purkinje cells in the cerebellum, and GABA-ergic neurons in the neocortex (5,16,18,45).Because BDV establishes a persistent noncytolytic infection in various cell lines and primary neurons and astrocytes in vitro (6,20,34), the mechanisms of neuronal degeneration in vivo remain unclear. Previous studies have indicated that even if the virus does not infect microglia in vivo, neonatal BDV infection is associated with strong microgliosis (6, 22, 38). Intriguingly, BDV-associated microgliosis has been found predominantly in areas of significant neuronal loss, i.e., cortex, hippocampus, and cerebellum (22,33,38,44), leading to the hypothesis that microglia activation plays a central role in BDV-associated neuronal damage (38,44).Microglia, the resident macrophage population in the brain, play a central role ...

show abstract

Alterations in neurotrophin and neurotrophin receptor gene expression patterns in the rat central nervous system following perinatal Borna disease virus infection

Cited by 54 publications

References 64 publications

Borna Disease Virus Replication in Organotypic Hippocampal Slice Cultures from Rats Results in Selective Damage of Dentate Granule Cells

Borna Disease Virus Replication in Organotypic Hippocampal Slice Cultures from Rats Results in Selective Damage of Dentate Granule Cells

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

Activation of Microglia by Borna Disease Virus Infection: In Vitro Study

Contact Info

Product

Resources

About