Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus-infected Lewis rats: a model of autism

Pletnikov, Mikhail V.; Rubin, Steven A.; Vasudevan, Kuzhalini; Moran, Timothy H.; Carbone, Kathryn M.

doi:10.1016/s0166-4328(98)00111-9

Cited by 113 publications

(87 citation statements)

References 25 publications

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“…In neonatally infected rats, BDV causes significant neuroanatomical disturbances characterized by degeneration of the dentate gyrus, cortical shrinkage, and cerebellar hypoplasia (13). It has been also demonstrated that neonatally infected rats show abnormal social play behavior, but not aggressive behavior, by the intruder-resident paradigm (12). A chronic astrocytosis and microgliosis were also demonstrated in neonatally infected rat brains (38).…”

Section: Discussionmentioning

confidence: 96%

“…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 provide an important paradigm for the investigation of the mechanisms by which virus infection induces neurobehavioral disorders.…”

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confidence: 99%

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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.

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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...

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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.

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“…Neurodevelopmental animal models like those developed for schizophrenia are now being brought to bear on autism. Some of these autism models are based on prenatal exposure to teratogens such as Borna disease virus [182] or valproic acid [119]. Others derive from findings of abnormal cerebellar anatomy in people with autism, and include both mutant animals with specific cerebellar malformations [49,139] and animals with surgical lesions of the midline cerebellum [32].…”

Section: Animal Modelsmentioning

confidence: 99%

Autism as a disorder of neural information processing: directions for research and targets for therapy

et al. 2004

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“…152,157,158 This model is particularly promising because behavioral features analogous to schizophrenia arise after a maturational latency, and then are normalized by administration of antipsychotic drugs. 157 Behavioral sequelae have been examined for a var-iety of experimental prenatal or postnatal infections including herpes simplex I, 103,164,165 LCMV, [166][167][168] Borna disease virus, 105,169,170 and Vesicular stomatitis virus. 104 Although there is no lack of data demonstrating that prenatal infections can profoundly disturb adult behavior, there is a salient need to meld these findings with new experimental advances in modeling schizophrenia, and thus begin to examine the effects of antipsychotic medications on virus-induced behavioral disturbances.…”

Section: Behavioral and Neuropsychologicalmentioning

confidence: 99%

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

Pearce

2001

Mol Psychiatry

137

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The task of defining schizophrenia pathogenesis has fascinated and frustrated researchers for nearly a century. In recent years, unprecedented advances from diverse fields of study have given credence to both viral and developmental theories. This review considers possible mechanisms by which viral and developmental processes may interact to engender schizophrenia. Many of the current controversies in schizophrenia pathogenesis are reviewed in light of the viral hypothesis, including: epidemiological findings and the role of a genetic diathesis, phenotype heterogeneity, abnormalities in excitatory and inhibitory neurotransmitter systems, anomalous cerebral latereralization, and static vs progressive disease. The importance of animal models in elucidating the impact of viral infections on developing neurons is illustrated by recent studies in which neonatal rats are infected with lymphocytic choriomeningitis virus in order to examine alterations in hippocampal circuitry. Finally, consideration is given to a new hypothesis that some cases of schizophrenia could be instigated by a viral infection that disrupts developing inhibitory circuits, consequently unleashing glutamatergic neurotransmission leading to selective excitotoxicity, and a degenerative disease course. Molecular Psychiatry (2001) 6, 634-646.

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Developmental brain injury associated with abnormal play behavior in neonatally Borna disease virus-infected Lewis rats: a model of autism

Cited by 113 publications

References 25 publications

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

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

Autism as a disorder of neural information processing: directions for research and targets for therapy

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

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