Journal of Virology, April 2000, p. 3441-3448, Vol. 74, No. 8
Unité des Virus Lents, CNRS URA 1930, Institut Pasteur, Paris, France,1 and
Department of Neuropharmacology, Division of Virology, The
Scripps Research Institute,2 and
Department of Neurosciences, University of California, San
Diego,3 La Jolla, California
Received 27 September 1999/Accepted 18 January 2000
Borna disease virus (BDV) infection of newborn rats leads to a
persistent infection of the brain, which is associated with behavioral
and neuroanatonomical abnormalities. These disorders occur in the
absence of lymphoid cell infiltrates, and BDV-induced cell damage is
restricted to defined brain areas. To investigate if damage to synaptic
structures anteceded neuronal loss in BDV neonatally infected rats, we
analyzed at different times postinfection the expression levels of
growth-associated protein 43 and synaptophysin, two molecules involved
in neuroplasticity processes. We found that BDV induced a progressive
and marked decrease in the expression of these synaptic markers, which
was followed by a significant loss of cortical neurons. Our findings
suggest that BDV persistent infection interferes with neuroplasticity
processes in specific cell populations. This, in turn, could affect the
proper supply of growth factors and other molecules required for
survival of selective neuronal populations within the cortex and limbic
system structures.
Borna disease virus (BDV)
is a nonsegmented, negative-stranded RNA virus, prototype of a new
family, Bornaviridae, within the order
Mononegavirales (9, 39). In a wide variety of
animal species, BDV causes central nervous system (CNS) disease
characterized by behavioral abnormalities and diverse pathology
(20, 35). There is evidence that BDV can infect humans, and
some data suggest that it might be associated with certain
neuropsychiatric disorders (3, 4, 10, 11, 24, 26, 34, 37).
Adult Lewis rats experimentally infected with BDV develop an immune
system-mediated biphasic behavioral disease (31, 40). In
contrast, neonatally infected rats develop a persistent tolerant
infection (PTI) associated with distinct behavioral and neuroanatomical
disturbances without encephalitis (1, 2, 6, 14, 31). Hence,
the BDV PTI model offers the possibility to investigate direct effects
of BDV infection on brain function in the absence of
immunopathology-related brain damage.
BDV exhibits a noncytolytic multiplication in all culture cell systems
assayed to date. However, BDV persistence in the rat brain is
associated with discrete neuronal damage, limited to specific
neuroanatomic areas. Rats with BDV PTI display cortical shrinkage,
cerebellar hypoplasia and degeneration of granule cell neurons of the
dentate gyrus (DG) (1, 2, 36). There is also evidence that
Purkinje cell neurons of the cerebellum degenerate (15). The
mechanisms involved in BDV-mediated degeneration of specific neuronal
populations are unknown. The proliferating properties of the targeted
neurons may play a role in this virally induced cell death
(21). Brains of rats with BDV PTI are characterized by a
chronic astrocytosis and microgliosis, as well as a sustained upregulation of specific proinflammatory cytokines (38).
Moreover, the expression level of tissue factor, which is likely to
play important roles in brain homeostasis and plasticity, is strongly increased in the brains of rats with PTI (19). Nevertheless, the cellular and molecular bases for the cognitive impairment of rats
with BDV PTI remain to be determined. In this study, we examined
whether persistent BDV infection affected synaptic density and neuronal
plasticity, both of which have been implicated in neural functions such
as learning and memory. The growth-associated protein 43 (GAP-43) and
synaptophysin (SYN) are well-established reliable markers of
neuroplasticity and synaptic density, respectively (18, 27, 29,
41). GAP-43 is a presynaptic membrane phosphoprotein which
accumulates in neuronal growth cones. SYN is a 38-kDa calcium-binding protein present in the membranes of presynaptic vesicles. GAP-43 and
SYN immunoreactivity (IR) can be used to estimate neuronal plasticity
and the number of synaptic events, respectively. Here, we report a
semiquantitative assessment of SYN and GAP-43 IR in BDV- and
sham-infected rats. We show that BDV neonatally infected rats display a
progressive decrease in synaptic density and plasticity, especially in
cortex and hippocampus, which preceded a significant dropout of
cortical neurons in infected rats. We discuss the implications of these
findings in the context of BDV-induced cognitive impairment in rats
with PTI.
Infection of rats.
Litters of Lewis rat pups (Charles River
Laboratories, Hollister, Calif., and St. Aubin les Elbeuf, France) were
inoculated intracranially, within 24 h of birth, with either a
20% (wt/vol) stock of BDV-infected rat brain homogenate or virus
diluent as a control (sham inoculation). We used the fourth brain
passage in newborn rats of the Giessen strain He/80 (17).
Procedures used for infections were as described elsewhere
(19).
Preparation of tissue for histology.
On days 7, 10, 15, 21, 25, 35, 40, 45, and 60 postinoculation (p.i.), the rats were deeply
anesthetized and perfused with phosphate-buffered saline followed by
4% paraformaldehyde. The brains were removed and postfixed in the same
solution before being dehydrated and embedded in paraffin, using
standard histological procedures (5). Sections (5 to 7 µm
thick) were cut with a rotary microtome, mounted onto Superfrost Plus
slides (Fisher Scientific, Pittsburg, Pa.), and stored at 4°C before
use. Adjacent series of sections for each animal were incubated with
the indicated antibodies.
Immunohistochemistry.
Procedures were similar to those
previously described (11, 12). Briefly, sections were baked
at 65°C for 1 h, deparaffinized in xylene, and hydrated. They
were treated for 30 min in methanol containing 0.3%
H2O2 to quench endogenous peroxidase activity and washed extensively in Tris-buffered saline (TBS). After a blocking
step for 1 h in TBS containing 3% horse serum, the sections were
incubated overnight at 4°C with monoclonal anti-GAP-43 (diluted 1:100; Sigma-Aldrich, St. Louis, Mo.) or anti-SYN (diluted 1:5; Boehringer Mannheim, Meylan, France) diluted in TBS. Subsequently, the
sections were incubated in biotinylated horse anti-mouse immunoglobulin G (diluted 1:75; Vector Laboratories, Burlingame, Calif.), followed by
an avidin-biotin-peroxidase complex (diluted 1:100; Vector Laboratories), for 45 min each. Between each incubation, the sections were extensively washed in TBS. Peroxidase activity was revealed by
immersing the slides in 0.5 mg of diaminobenzidine (Sigma-Aldrich) per
ml in 100 mM Tris-HCl (pH 7.4) containing 0.03%
H2O2, and the sections were dehydrated and
mounted in Eukitt (Kindler GmbH & Co., Freiburg, Germany). Stainings
with the BDV nucleoprotein (11) and glial fibrillary acidic
protein (GFAP; Dakopatts, Carpinteria, Calif.) rabbit antibodies were
done similarly, with the following modifications: (i) the sections were
permeabilized by treatment with 0.5% Triton before staining, (ii) we
used a biotinylated goat anti-rabbit secondary antibody (diluted 1:100;
Vector Laboratories), and (iii) sections were counterstained with
Harris hematoxylin before mounting. Parvalbumin expression was assessed
by incubation with a monoclonal antiparvalbumin antibody (diluted
1:2,000; Sigma-Aldrich), followed by incubation with a fluorescein
isothiocyanate-conjugated anti-mouse immunoglobulin G (diluted 1:500;
Diagnostics Pasteur, Marnes-la-Coquette, France). After extensive
washes in TBS, the sections were mounted in Vectashield (Vector Laboratories).
Semiquantitative assessment of SYN and GAP-43 IR by
microdensitometry.
SYN and GAP-43 immunolabeled sections were
analyzed with a Leica 570 C Quantimet as described elsewhere
(28). Briefly, the average optical density (OD) of the
reaction product was measured in six different fields, including the
frontal cortex, molecular layer of the hippocampus, granule cell layers
of the DG and cerebellum, thalamus (lateral posterior thalamic
nucleus), and basal ganglia (caudate putamen), for at least two
sections for each animal. The area of interest was delineated on the
video screen with a mouse-type cursor. All OD measurements were done
under the same optical and lighting conditions. The OD of a blank field
in each slide was subtracted to arrive at a corrected OD value,
expressed as the percentage of the median of a given experimental
point. This procedure has been previously used by us and validated in experimental models of denervation and reinnervation (27),
as well as in human neurodegenerative disorders (29).
Morphometric analysis.
Neuronal cell counts were performed
in 5-µm-thick sections of five each control and infected rats (45 days p.i.) that were stained with cresyl violet, dehydrated, and
mounted in Eukitt. Quantitative analysis of the sections (cortical
thickness and number of cells) was done using the Leica 570 C Quantimet
as described elsewhere (42). Morphometric determinations of
the number of stained cells along the cortical ribbon for two sections
for each animal were determined using the 40× objective. This approach has been previously shown to yield results comparable to those obtained
by stereological procedures, but in addition provides information as to
cell size (16).
Statistical analysis.
For statistical analysis, we used the
nonparametric Mann-Whitney U test (from the Statview
package), with a minimum accepted level of significance of 0.05 (P < 0.05).
Clinical assessment of rats with BDV PTI.
A total of 120 rats
from 20 different litters were used in this study. All BDV- and
sham-infected rats appeared clinically healthy over the observation
period, except for the previously reported growth retardation in the
infected group (2). By the end of experiment, the weight of
BDV PTI rats was approximately 60% of the weight of the control littermates.
Altered GAP-43 and SYN expression in rats with BDV PTI.
To
determine if persistent BDV infection leads to synaptic damage,
sections from sham- and BDV-infected rats were immunolabeled with
antibodies against the synaptic marker, SYN, and the marker of
neuroplasticity and regeneration, GAP-43. Consistent with previous studies (27), SYN and GAP-43 immunolabeled the neuropil with a characteristic granular pattern, following a laminar distribution (Fig. 1). Semiquantitative analysis
revealed that IR (expressed as mean ± standard error of the mean
[SEM]) for GAP-43 (Fig. 2) and SYN
(Fig. 3) were both selectively decreased
in specific CNS areas of infected animals. Decrease of these two
markers in the DG paralleled the kinetics of DG granule cell
degeneration previously found in rats with BDV PTI (2). In
addition, GAP-43 expression was decreased in the cortex and hippocampus
and was unchanged in the thalamus, cerebellum, and basal ganglia (Fig.
2), whereas SYN IR was decreased in the cortex, hippocampus, and
thalamus of infected animals but unchanged in the cerebellum and basal ganglia (Fig. 3). Moreover, a closer observation of SYN immunostaining revealed an abnormal pattern in the distribution of its IR in BDV-infected animals (Fig. 4). SYN IR,
which usually accumulates in synaptic terminals, was clustered in the
inner molecular layer of the DG and also present in the cell bodies of
DG granule neurons by 25 days p.i., prior to their degeneration (Fig.
4B and D). By day 45 p.i., SYN was also found accumulating in
dystrophic axon figures in the corpus callosum, which are often linked
with axonal transport dysfunction (Fig. 4F). Such axonal spheroids were
also observed more occasionally within the neocortex (not shown).
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Synaptic Pathology in Borna Disease Virus
Persistent Infection
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
RESULTS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
View larger version (103K):
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FIG. 1.
Distribution of GAP-43 and SYN IR in sham- and
neonatally BDV-infected rats, 40 days p.i. Cortex (A to D) and
hippocampus (E to H) from control and infected rats exhibit the
characteristic granular immunolabeling of the neuropil but not the cell
bodies. Magnification, ×100.
View larger version (37K):
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FIG. 2.
Quantitative analysis of GAP-43 IR in the cortex,
hippocampus, DG, thalamus, cerebellum, and basal ganglia from control
and BDV-infected rats. Values of pixel intensities (percentage of
median) are mean ± SEM, each bar representing the result of at
least eight independent measurements. Double (P < 0.05) and triple (P < 0.005) asterisks indicate
the level of statistical significance (determined by the Mann-Whitney
U test). Loss of GAP-43 IR in the DG of neonatally infected
rats followed the kinetics of DG granule cell degeneration observed in
these animals. Compared to age-matched controls, GAP-43 levels are
significantly reduced in the cortex and hippocampus starting at about
day 25 p.i. No significant differences are observed elsewhere.
View larger version (34K):
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FIG. 3.
Quantitative analysis of SYN IR in the cortex,
hippocampus, DG, thalamus, cerebellum, and basal ganglia from control
and BDV-infected rats. Values of pixel intensities (percentage of
median) are mean ± SEM, each bar representing the result of at
least eight independent measurements. Double asterisks (P < 0.05) indicate the level of statistical significance
(determined by the Mann-Whitney U test). Loss of SYN IR in
the DG of neonatally infected rats precedes and follows the kinetics of
DG granule cell degeneration observed in these animals. Compared to
age-matched controls, SYN levels are significantly reduced in the
cortex, hippocampus, and thalamus.
View larger version (122K):
[in a new window]
FIG. 4.
Abnormal SYN immunostaining in BDV-infected rat brain.
Note the clustering of SYN IR within the inner molecular layer of the
DG at 25 days p.i. (compare panels A and B). SYN staining is also found
in the cell bodies of dentate granule cells (arrowed cells in panel D,
shown at a larger magnification in the boxed area). By day 45 p.i., the corpus callosum, which is usually negative for SYN staining
in control rats (panel E), exhibits a patched IR in infected animals
(arrows in panel F and boxed area). The immunostaining accumulates in
axonal blobs, indicating an abnormal axoplasmic flow and a poor
transport of SYN to the synaptic terminals. Magnification, ×150.
Patterns of neuronal loss in BDV-infected rats.
To examine the
impact of synaptic density and plasticity alterations on neuronal
viability, sections from sham- and BDV-infected rats were stained with
cresyl violet and analyzed with a Quantimet 570C (Fig.
5A). We found that by day 45 p.i.,
BDV-infected animals exhibited a marked cortical shrinkage (about
30%), accompanied by a selective loss of cells with a diameter of
greater than 100 µm (P < 0.01) (Fig. 5A). Based on
their size, it is probable that dying cells were cortical neurons.
Moreover, staining with an antibody, specific to parvalbumin, a
calcium-binding protein present in virtually all gamma-aminobutyric
acid (GABA)-ergic neurons in the cortex (7), showed that
this neuronal population was severely depleted in BDV-infected rats by
day 45 p.i. (Fig. 5B).
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Viral load and degree of astrocytosis in rats with BDV PTI.
To
study the load and distribution of BDV antigen and the degree of
reactive astrogliosis in the brains of BDV PTI and control rats,
sections from BDV-infected and sham-inoculated control rats were
immunolabeled with antibodies against the BDV nucleoprotein and GFAP, a
marker for astrocytes (Fig. 6).
Consistent with previous findings by us and others (1, 15,
38), soon after inoculation (7 to 15 days p.i.), expression of
BDV antigen was mainly localized to limited regions of the brain, i.e.,
the cortex, CA3 and CA4 regions of the hippocampus, and Purkinje cells
of the cerebellum (not shown). By 3 weeks p.i., BDV antigen was
strongly expressed in virtually all brain areas (Fig. 6A), with no
apparent decrease of expression level over time. Viral antigen was
detected within the cell bodies. As previously described, we also
observed a more diffuse staining of the tissue, likely due to high
levels of viral nucleoprotein in the neuropil (38). Of
interest, only low levels of BDV antigen expression were detected in
neurons of the DG prior to their degeneration (not shown). No staining
was seen in sham-inoculated animals. Immunostaining with the GFAP
antibody confirmed the previously described (19)
upregulation of GFAP expression in brains of rats with BDV PTI by
3 weeks p.i. (Fig. 6B). Astrogliosis was most prominent in the
hippocampus, cortex, and cerebellum of BDV-infected rats.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Viral infections of the CNS can cause behavioral disturbances that are associated with specific neuronal injury (25, 30, 43). This neuronal damage can occur as a result of direct cytolysis due to virus multiplication or as a consequence of the host immune responses against the infectious agent (22, 44). However, viruses can also persist in the CNS in the absence of the hallmarks of cell destruction and inflammation, but causing disturbances in specialized functions of cells (13, 32, 33). This, in turn, can disrupt CNS homeostasis and alter normal brain function. Thus, we have previously reported that persistent lymphocytic choriomeningitis virus infection of the mouse CNS causes altered synaptic plasticity and cognitive function without destruction of brain cells (12).
Neonatal BDV infection of the rat provides an important system to study the mechanisms whereby viruses can interfere with cognitive, neurodevelopmental, and behavioral functions of the CNS without encephalitis (1). In this study, we have shown that rats with BDV PTI display significant alterations in the expression levels of GAP-43 and SYN, two molecules that play key roles in synaptic density and plasticity (18, 27, 29, 41). These virally mediated disturbances in synaptic protein expression were restricted mainly to the limbic system and did not appear to correlate directly with either viral load or astrogliosis. Thus, GAP-43 and SYN levels of expression were not altered in the cerebellum of infected rats, despite a prominent astrocytosis and high viral load in this brain region. The progressive loss of neurons in DG and cortex likely contributed to the decreased expression of GAP-43 and SYN. However, a downregulation in the expression of these synaptic markers preceded the observed neuronal degeneration.
Closer examination of SYN staining showed that by 3 weeks p.i., neurons appeared to be affected in axonal transport, as revealed by the accumulation of this protein in the cell bodies of granule cells in the DG, or in axonal spheroids in the corpus callosum. This is consistent with the cholinergic abnormalities found by Gies et al. in brains of BDV acutely infected rats, prior to the onset of encephalitis (17). These cholinergic abnormalities had also been linked to abnormal axoplasmic flow, suggesting that BDV infection of neurons may interfere with such processes.
Morphometric analysis showed a loss of about 30% of neuronal bodies in the cortical area of rats with PTI, indicating that contrary to the commonly accepted idea, BDV persistence causes a progressive neuronal degeneration in areas outside the DG and cerebellum. The selective decrease in cells with a diameter of >100 µm and with positive parvalbumin staining suggest that both pyramidal and GABA-ergic cortical neurons exhibit selective vulnerability to BDV infection. It is worth noting that a 15% reduction in cortical neurons, lower than the reduction described here, has been associated with cognitive impairment in rats (8). There is compelling evidence, both in cultured cells and in vivo, that BDV is noncytolytic (2, 23). Based on the findings reported here, it is plausible that BDV-induced synaptic and axoplasmic flow damage leads to impairment in the uptake and trafficking of growth factors required for proper neuronal function. This, in turn, may result in degeneration of specific neuronal populations. Localized synaptic alterations were apparent at a time when virus antigen was present in virtually all brain areas. Therefore, different neuronal populations may differ in vulnerability to a number of factors, including not only viral load and reactive astrocytosis but likely also local changes in the production of cytokines and other molecules involved in maintaining proper brain function. This, in turn, may promote regional alteration in neural cell communication, leading to injury.
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ACKNOWLEDGMENTS |
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This work was supported by grants from the Ministère de l'Education Nationale, de la Recherche et de la Technologie (program PRFMMIP) and by the Institut Pasteur and the Centre National de la Recherche Scientifique (D.G.D. and S.S.); by grant NS12428 (J.C.T.); by grants AG5131, AG10689, MH45294, MH59745, and DA 12065 (E.M.); and by an Overseas Researcher Scholarship from the Ministry of Education, Science, Sports and Culture of Japan (M.W.).
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FOOTNOTES |
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* Corresponding author. Mailing address for Daniel Gonzalez Dunia: Unité des Virus Lents, Institut Pasteur, 28, rue du Dr Roux, 75724 Paris Cedex 15, France. Phone: 33 1 45 68 87 71. Fax: 33 1 40 61 31 67. E-mail: ddune{at}pasteur.fr. Mailing address for Juan Carlos de la Torre: The Scripps Research Institute, IMM6, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9462. Fax: (858) 784-9981. E-mail: juanct{at}scripps.edu.
Present address: Department of Neurovirology, Research Institute
for Microbial Diseases, Osaka University, Osaka, Japan.
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REFERENCES |
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Materials and Methods
Results
Discussion
References
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Journal of Virology, April 2000, p. 3441-3448, Vol. 74, No. 8
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