Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits

Rubin, Steven A.; Sylves, Peter; Vogel, Michael W.; Pletnikov, Michael; Moran, Timothy H.; Schwartz, Gray J; Carbone, Kathryn M.

doi:10.1016/s0361-9230(98)00133-6

Cited by 75 publications

(55 citation statements)

References 57 publications

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“…Furthermore, it is known that some strains of mice exhibit locomotor hyperactivity after BDV infection (11). 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).…”

Section: Discussionmentioning

confidence: 97%

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: 97%

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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“…For example, it has been shown that neonatal inoculation with Cytomegalovirus, Herpes simplex virus type 1, or the bacterial endotoxin lipopolysaccharide (LPS), led in the adult offspring to disrupted prepulse inhibition (PPI), considered to model sensorimotor gating deficits in schizophrenia (Borrell et al, 2002;Engel et al, 2000;Rothschild et al, 1999). Other studies have shown that prenatal inoculation with human influenza virus and neonatal inoculation with Borna disease virus or Lymphocytic Choriomeningitis virus led to abnormal temporolimbic morphology, such as reduced thickness of the hippocampus, dentate gyrus, and entorhinal cortex (Fatemi et al, 1999;Pearce et al, 2000;Rubin et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia

Zuckerman

Rehavi

Nachman

et al. 2003

Neuropsychopharmacol

438

355

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Prenatal exposure to infection is associated with increased liability to schizophrenia, and it is believed that such an association is mediated by the maternal immune response, in particular, the proinflammatory cytokines released by the maternal immune system, which may disrupt fetal brain development. Impaired capacity to ignore irrelevant stimuli is one of the central deficits in schizophrenia, and is manifested, among others, in loss of latent inhibition (LI), a phenomenon whereby repeated inconsequential pre-exposure to a stimulus impairs its subsequent capacity to signal significant consequences. We tested the effects of prenatal immune activation induced by peripheral administration of the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I : C) to pregnant dams, on LI in juvenile and adult offspring. Consistent with the characteristic maturational delay of schizophrenia, prenatal immune activation did not affect LI in the juvenile offspring, but led to LI disruption in adulthood. Both haloperidol (0.1 mg/kg) and clozapine (5 mg/kg) reinstated LI in the adult offspring. In addition, prenatal immune activation led to a postpubertal emergence of increased sensitivity to the locomotorstimulating effects of amphetamine and increased in vitro striatal dopamine release, as well as to morphological alterations in the hippocampus and the entorhinal cortex in the adult offspring, consistent with the well-documented mesolimbic dopaminergic and temporolimbic pathology in schizophrenia. These results suggest that prenatal poly I : C administration may provide a neurodevelopmental model of schizophrenia that reproduces a putative inducing factor; mimics the temporal course as well as some central abnormalities of the disorder; and predicts responsiveness to antipsychotic drugs.

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“…In the present study, we investigated LTP and DP of both EPSP slope and PS amplitude in vivo in the DG area of prenatally salineand morphine-exposed juvenile rat offspring. We also evaluated spatial memory in these offspring using a two-trial Y-maze test (Dellu et al, 1997), since the DG area of the hippocampus has been associated with spatial memory (Colicos and Dash, 1996;Nilsson et al, 1999;Rubin et al, 1999). Finally we determined whether GABA-containing neurons in the DG area, which largely control the EPSP/spike relationship (Tomasulo et al, 1991;Marder and Buonomano, 2004) and the functions of dentate granule cells (Coulter and Carlson, 2007), would be alternated by prenatal morphine exposure.…”

Section: Introductionmentioning

confidence: 99%

Impaired in vivo synaptic plasticity in dentate gyrus and spatial memory in juvenile rats induced by prenatal morphine exposure

et al. 2008

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ABSTRACT:Prenatal morphine exposure induces neurobiological changes, including deficits in learning and memory, in juvenile rat offspring. However the effects of this exposure on hippocampal plasticity, which is critical for learning and memory processes, are not well understood. The present study investigates the alterations of spatial memory and in vivo hippocampal synaptic plasticity in juvenile rats prenatally exposed to morphine. On gestation days 11-18, pregnant rats were randomly chosen to be injected twice daily with morphine or saline. Each juvenile offspring (postnatal day 22-31) performed one two-trial Y-maze task to evaluate spatial memory. Afterwards, the in vivo field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded in the perforant path dentate gyrus (DG) pathway in the hippocampus. Prenatal morphine exposure reduced depotentiation (DP), but not longterm potentiation (LTP), of the EPSP slope. However, both LTP and DP of the EPSP slope were depressed in prenatal morphine-exposed juvenile offspring. The morphine group also showed poorer performance for the Y-maze task than the control group. Depressed PS LTP, but not EPSP LTP, in the morphine group suggested that prenatal morphine exposure changed GABAergic inhibition, which mediates EPSP-spike potentiation. Then a loss of GABA-containing neurons in the DG area of the morphine group was observed using immunohistochemistry. Taken together, our results suggest that prenatal morphine exposure impairs the juvenile offspring's dentate synaptic plasticity and spatial memory, and that decreased GABAergic inhibition may play a role in these effects. These findings might contribute to an explanation for the cognitive deficits in children whose mothers abuse opiates during pregnancy. V V C 2008 WileyLiss, Inc.

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Borna disease virus-induced hippocampal dentate gyrus damage is associated with spatial learning and memory deficits

Cited by 75 publications

References 57 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

Immune Activation During Pregnancy in Rats Leads to a PostPubertal Emergence of Disrupted Latent Inhibition, Dopaminergic Hyperfunction, and Altered Limbic Morphology in the Offspring: A Novel Neurodevelopmental Model of Schizophrenia

Impaired in vivo synaptic plasticity in dentate gyrus and spatial memory in juvenile rats induced by prenatal morphine exposure

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