close

Вход

Забыли?

вход по аккаунту

?

Cognitive dysfunction in mice deficient for TNF- and its receptors.

код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1056 –1064 (2008)
Cognitive Dysfunction in Mice Deficient for TNF- and
Its Receptors
Bernhard T. Baune,1,2* Florian Wiede,3 Anja Braun,1 Jonathan Golledge,4 Volker Arolt,2 and Heinrich Koerner3
1
Psychogenetics Research Unit, School of Medicine and Comparative Genomics Centre, James Cook University, Townsville, Australia
Department of Psychiatry, University of Muenster, Muenster, Germany
3
Comparative Genomics Centre, School of Pharmacy and Molecular Sciences/School of Veterinary and Biomedical Sciences, James
Cook University, Townsville, Australia
4
Vascular Biology Unit, School of Medicine, James Cook University, Townsville, Australia
2
Recent evidence suggests a role for tumor necrosis factor alpha (TNF) in the functioning of the
central nervous system (CNS). The aim of this
work was to examine the effect of a deficiency of
TNF (TNF/) and its main receptors (TNF-R1/
and TNF-R2/) on cognitive function. A standardized survey on cognition-like behavior assessing
learning and retention, spatial learning/memory,
cognitive flexibility, and learning effectiveness
was used in B6.WT and B6.TNF gene targeted mice
strains (B6.wild-type, B6.TNF/, B6.TNF-R1/,
B6.TNF-R2/ mice). All studied mice strains
demonstrated successful exploration and learning processes during the training phases of the
tests, which made the specific cognition-like tests
valid in these mice strains. In the specific cognition-like tests, the B6.TNF/ mice demonstrated
significantly poorer learning and retention in the
novel object test compared to B6.WT, B6.TNF-R1/
and B6.TNF-R2/ mice. In addition, spatial
learning and learning effectiveness were significantly poorer in B6.TNF/ mice compared to
B6.WT mice. Moreover, the moderately impaired
cognitive performance with similar degrees in
B6.TNF-R1/ or B6.TNF-R2/ mice was generally
better than in TNF/ mice but also poorer than
in B6.WT mice. While the absence of TNF was
correlated with poor cognitive functioning, the
deletion of both TNF-receptors was involved in
partially reduced cognitive functioning. Lowlevels of TNF under non-inflammatory immune
conditions appear essential for normal cognitive
function. TNF displays an interesting candidate gene for cognitive function. Translational
research is required to investigate associations
between genetic variants of TNF and cognitive
function in healthy subjects and neuropsychiatric
samples.
ß 2008 Wiley-Liss, Inc.
This article contains supplementary material, which may be
viewed at the American Journal of Medical Genetics website at
http://www.interscience.wiley.com/jpages/1552-4841/suppmat/
index.html.
*Correspondence to: Bernhard T. Baune, Associate Professor,
Psychogenetics Research Unit, School of Medicine and Comparative Genomics Centre, James Cook University, Townsville, QLD
4811, Australia. E-mail: bernhard.baune@jcu.edu.au
Received 13 October 2007; Accepted 13 December 2007
DOI 10.1002/ajmg.b.30712
Published online 19 February 2008 in Wiley InterScience
(www.interscience.wiley.com)
ß 2008 Wiley-Liss, Inc.
KEY WORDS:
cognitive function; memory; learning; TNF; neuroscience; signaling;
TNF receptors
Please cite this article as follows: Baune BT, Wiede F,
Braun A, Golledge J, Arolt V, Koerner H. 2008. Cognitive
Dysfunction in Mice Deficient for TNF- and Its Receptors. Am J Med Genet Part B 147B:1056–1064.
INTRODUCTION
Cytokines have been implicated in immune, inflammatory,
and more recently, central nervous system (CNS) function
[Hopkins and Rothwell, 1995; Rothwell and Hopkins, 1995;
Rothwell, 1999; Pollmacher et al., 2002]. More notably,
cytokines have been associated with numerous pathological
states within the CNS, such as autoimmune disease (i.e.,
multiple sclerosis), stroke, trauma, neurodegenerative disease
(i.e., Alzheimer’s disease) [Rothwell and Loddick, 2002;
Ransohoff and Benveniste, 2006], depression [Hickie and
Lloyd, 1995; Kronfol and Remick, 2000; Capuron and Dantzer,
2003; Raison et al., 2006; Irwin and Miller, 2007], and cognitive
dysfunction [Baune et al., 2007; Baune et al., in press].
The cytokine tumor necrosis factor alpha (TNF) is expressed
in a widespread pattern within the brain [Tonelli and Postolache, 2005] and is of particular interest to CNS function since it
is constitutively expressed and appears to be involved in the
modulation of neuronal activities in the normal human brain
[Dunn et al., 1999; McCann et al., 2000]. Furthermore, it has
been suggested that the continual presence of TNF is required
for preservation of synaptic strengths at the excitatory synapse
[Beattie et al., 2002]. In the CNS, TNF develops its effects
through various mechanisms. Through its effects on AMPA
(alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
receptor trafficking, TNF may affect synaptic plasticity and
be modulating the response to neural injury [Beattie et al.,
2002]. Recent research demonstrated that synaptic scaling is
altered by TNF [Stellwagen and Malenka, 2006] and that
changes in long-term potentiation (LTP) in the dorsal horn of
the spinal cord are altered by TNF as well as changes in
neurotransmitter metabolism, and neuro-developmental processes [Stellwagen and Malenka, 2006].
In addition, the two distinctly different receptors, the TNFp55 receptor (TNF-p55R ¼ TNF-R1) and the TNF-p75 receptor
(TNF-p75R ¼ TNF-R2), both belonging to the TNF/nerve
growth factor receptor family mediate TNF effects in the
CNS [Aggarwal et al., 2000]. Both receptors exist as transmembrane and soluble forms, the latter arising from cleavage
of the transmembrane forms [Kohno et al., 1990; Nophar et al.,
1990]. The TNF-R1 contains an intracellular death domain
[Tartaglia et al., 1993] and primarily results in apoptosis
TNF Deficiency and Cognition
through activation of caspases [Chinnaiyan et al., 1995; Hsu
et al., 1995, 1996]. Signaling through the TNF-R2 can be
neuroprotective [Bernardino et al., 2005] by inhibiting apoptosis induction [Liston et al., 1996] via effects on caspases, at
least in vitro [Roy et al., 1997]. Under pathological conditions,
TNF and both types of TNF receptors play a role in cell survival
and inflammation in the injured and diseased CNS [Owens
et al., 2001; Hallenbeck, 2002] leading to the assumption of
both neuroprotective [Bruce et al., 1996; Gary et al., 1998;
Pradillo et al., 2005] and neurotoxic [Dawson et al., 1996;
Barone et al., 1997; Nawashiro et al., 1997; Lavine et al.,
1998; Yang et al., 1998] effects of TNF with examples in spinal
cord re-grow [Schwartz et al., 1991, 1994], protection of
mesencephalic neurons from glutamate neurotoxicity [Shipno
et al., 1999] and pro-survival effects of TNF in the retina
following ischemia-reperfusion damage [Diem et al., 2001;
Fontaine et al., 2002].
It is assumed that through those mechanisms and pathways,
TNF is involved in several processes relevant to cognition in
the normal brain, including neuronal viability [Saha and
Pahan, 2003], neurotransmitter production [Dunn et al.,
1999], neuroendocrine responses [McCann et al., 2000], and
modulation of neuronal and glial cell function [Griffin et al.,
1998].
In previous research, after activation of the immune system,
increased levels of TNF have been related to cognitive
dysfunction in TNF over-expressing rodent models [Fiore
et al., 1996; Aloe et al., 1999; Matsumoto et al., 2002] and in
humans [Bruunsgaard et al., 1999]. Although these previous
findings suggested involvement of TNF with various CNS
functions at the protein level, little knowledge has been gained
on the genetic effects of TNF on cognitive function under
unchallenged immunological conditions. A recent genetic
study by this group suggested that genetic variants of TNF
were associated with processing speed in healthy subjects
despite normal serum levels of TNF [Baune et al., in press].
Further analyses of molecular effects of TNF on cognitive
function that also involves TNF pathways such as TNF
receptors 1 and 2 at a genetic level might contribute to the
emerging evidence for a role of TNF in the unchallenged CNS
and more specifically in cognitive function.
In this animal study we investigated how TNF affects
cognitive function in the absence of an inflammatory response.
The aim of this study was to examine the role of TNF signaling
in mediating cognitive function-like behaviors in mice. It was
hypothesized that the absence of TNF and its receptors TNFR1 and TNF-R2 was related to poorer cognitive function. We
utilized mice deficient in TNF and its receptors and compared
cognition-like behavior in these animals by comparison to wild
types. Our results show that under unchallenged immune
conditions the presence of TNF and its receptors TNF-R1 and
TNF-R2 is essential for normal cognitive function.
MATERIALS AND METHODS
Mouse Strains
The gene-targeted C57BL/6 mouse strains deficient for TNF
(B6.TNF/) and lymphotoxin-a (B6.LTa/) were generated
on a genetically pure C57BL/6 (B6 ¼ C57BL/6) background as
described [Korner et al., 1997; Sean Riminton et al., 1998].
Both mouse strains were screened as previously published
[Sean Riminton et al., 1998; Wilhelm et al., 2001]. The B6.TNFR1/ (Jackson stock number: 003242) [Peschon et al., 1998]
and B6.TNF-R2/ mice (Jackson stock number: 002620)
[Erickson et al., 1994] were obtained from Jackson Laboratories (Bar Harbor, ME) and were also established on a C57BL/6
background or backcrossed. The screening procedure followed
the protocol provided by Jackson Laboratories as published
1057
previously [Erickson et al., 1994; Peschon et al., 1998]. The
B6.WT mice were obtained directly from the supplier (Jackson). All experimental mice were bred and kept at the Animal
Research Facility of the Comparative Genomics Center under
specific pathogen free (SPF) conditions. Mice of 8–12 weeks of
age were used in all experiments.
Animal procedures were approved by the James Cook
University Animal Ethics committee. All hand-scored data
were obtained by a researcher blinded to the genotype of the
experimental mice.
Gene Expression in the Brain
To test gene expression in the CNS, brains were removed and
four brain regions were dissected and immediately frozen in
liquid nitrogen: brain stem, hippocampus, cerebellum, and
frontal cortex. RNA was isolated with the PureLinkTM Microto-MidiTM Total RNA Purification System (Invitrogen, Sydney,
Australia) and cDNA was synthesized from 1 to 2 mg of
total RNA with the SuperScript1 III First-Strand Synthesis
System (Invitrogen) according to the manufacturer’s instructions. For this analysis B6.WT mice, B6.TNF/, B6.TNFR-1,
and B6.TNFR-2 were used, and specificity of the primers was
tested on B6.WT samples. PCR was performed with the
following primers: GAPDH (forward): 50 -ACCACAGTCCATGCCATCAC-0 3, GAPDH (reverse): 50 -TCCACCACCCTGTTGCTGA-0 3; TNF (forward): 50 -CCACCACGCTCTTCTGTCTACTGA-0 3, TNF (reverse): 50 -ACCACTAGTTGGTTGTCTTTGAGAT-0 3; RTF-R1 (TNF-R1 forward): 50 -GCAGTGTCTCAGTTGCAAGACATGTCGG-0 3, RTR-R1 (TNF-R1 reverse): 50 CGTTGGAACTGGTTCTCCTTACAGCCAC-0 3; RTF-R2 (TNFR2 forward): 50 -ACAGTGCCCGCCCAGGTTGTCTTG-0 3, RTRR2 (TNF-R2 reverse): 50 -GCAGAAATGTTTCACATATTGGCCAGGAGG-0 3. The resulting products were visualized on
ethidium bromide-containing 1.5% agarose gels and photographed in a UV trans-illuminator. The patterns of expression
of TNF and its receptors in the brain are presented in the
Supplementary Figure 1 which shows the expression of TNF,
TNF-R1, and TNF-R2 in all four brains regions except in the
corresponding knock-out mice strains (Supplementary Fig. 1).
Peripheral Cytokine Assessment
Tail blood was taken from mice and serum was prepared for
analysis. Cytokine concentrations were measured using the
pro-inflammatory cytometric bead array (CBA, BD Biosciences, Sydney, Australia) specific for the cytokines IL-1b, IL-6,
IL-8, IL-10, IL-12p70, and TNF. The data were acquired with a
FacsCalibur flow cytometer (BD Biosciences) and analyzed
with Cell Quest software. Following acquisition and first
analysis sample results were generated in graphical and
tabular format using the BD CBA Analysis Software. The
intra-assay coefficients of variation were 4–7% for IL-1b, 5–8%
for IL-6, 2–5% for IL-8, 5–6% for IL-10, 3–6% for IL-12p70, and
6–10% for TNF. The inter-assay coefficients of variation were
8–13% for IL-1b, 8–10% for IL-6, 4–7% for IL-8, 8–11% for
IL-10, 6–9% for IL-12p70, and 8–15% for TNF.
Behavioral Test Procedures
The assessment of cognitive function in mice was carried out
with a survey on cognition-like behavior of mice according to
established and published procedures [McLay et al., 1998;
Holocomb et al., 1999; Tang et al., 2001; Wall and Messier,
2002; Simen et al., 2006]. The survey involved the established
home cage condition, the Open Field test (exploration under
more stressful conditions) [Simen et al., 2006], Novel Object
Recognition Test (retention memory) [Tang et al., 2001], and
the Barnes Maze test (spatial memory and learning) [McLay
1058
Baune et al.
et al., 1998]. Complete behavioral test results were obtained for
N ¼ 10 mice (five male; five female) per mice strain (four mice
strains equals N ¼ 40 in total). After each test the mice were
allowed to recover for at least 1 week before the next test. The
same mice were used for each test. Mean age (58.4–78.1 days)
and weight (23.9–27.8 g) did not differ between mice strains.
Home Cage Locomotor Activity Testing
Mice were tested individually between 8.00 and 10.00 am
under basal, non-stressful conditions for non-stressful general
locomotor activity in cages with >2-day-old home-cage bedding
according to published procedures [Simen et al., 2006]. Movements were digitally tracked using the ANY-maze Video
Tracking System (Stoelting Co., Wood Dale, IL). Total distance
moved and overall speed were calculated over a 5-min period
using ANY-maze behavioral analysis software (version 4.3;
Stoelting Co.).
Open Field Test
Under more stressful conditions and according to published
procedures [Simen et al., 2006] mice were placed in the center
of a brightly lit white Plexiglas box (15.75 in. 15.75 in.), and
their movements were tracked using ANY-maze (Stoelting Co.)
for 5 min. Distance traveled, speed and line crossing of the four
zones (Northwest; Northeast; Southwest; Southeast) of the
open field were calculated by the use of ANY-maze software
(version 4.5; Stoelting Co.).
Retention Memory: Novel Object Recognition
The Novel Object Recognition task was undertaken in
accordance to published protocols [Tang et al., 2001]. Before
training, mice were individually habituated by allowing them
to explore the open-field box for 5 min per session. Mice had
three sessions per day over 3 days. During the training session,
two novel objects were placed into the open-field 12 in. away
from each other (symmetrically), then the individual animal
was allowed to explore for 5 min. Exploring the object was
considered to occur when the head of the animal was facing and
within 1 in. of the object or any part of the body except the tail
was touching the object. Time spent exploring each object was
recorded. The animals were returned to their home cages
immediately after training. During the retention test which
was performed 24 hr after the training session, the animals
were individually placed back into the same open-field box, and
allowed to explore freely for 5 min. Before retention, one of the
familiar objects used during training was replaced by a novel
object. The two objects made of the same wooden material with
the similar color and smell, were different in shape but
identical in size. Moreover, the open-field and objects were
thoroughly cleaned using 70% alcohol after each session to
avoid possible odorant cues. A preference index, a ratio of the
amount of time spent exploring any one of the two items
(training session) or the novel object (retention session) over
the total time spent exploring both objects, was used to
measure recognition memory. A preference index > 1 was
regarded as successful learning and retention memory. Movements were tracked using ANY-maze (Stoelting Co.).
Spatial Memory and Learning: Barnes Maze
The Barnes Maze (Stoelting Co.) consists of a bright, circular
white platform (36 in.) with 20 holes and stand, one with a
hidden escape box. A key feature of the Barnes Maze is the
inclusion of false boxes that are too small to be entered but look
the same as the target box to the mouse. The false boxes remove
visual cues that might be observed through an open hole.
An imaging program (ANY-maze, US) was used to track
movements. Barnes Maze procedures were carried out over a
4-day period according to published protocols [McLay et al.,
1998].
Pre-training. Mice were pre-trained to enter the escape
box by (1) placement into the escape box for 2 min, (2) guidance
to the escape box, remaining for 2 min, and (3) placement
outside the escape box within a glass chamber for up to 3 min
and remained in the escape box for 2 min.
Training (4 trials/day for 4 days). The following day,
mice were briefly placed in the center of the maze under a
removable chamber and given 3 min to locate the escape box.
The number of errors (incorrect hole pokes), latency to locate
and enter the escape box, and the navigation patterns were
recorded. Mice that failed to enter the escape box within 3 min
were guided to the box where they remained for 2 min prior to
returning to their home cage. Mice received 4 trials/day,
separated by 15 min, for 4 days.
Probe trials. On the day after the last training test, two
probe trials were given for 3-min duration. The escape box was
rotated 1808 (probe trial 1) and 908 (probe trial 2) from the
original training position, respectively. Latency to the old and
new escape locations, exploration time of the old and new
escape boxes and errors were recorded.
Measures of Spatial Retention Memory and Learning
Spatial retention memory. Retention memory for the
(known) old escape box was considered as the tendency of the
mice to explore the old escape box in the probe trial instead of
exploring the new (unknown) box location. Thus, short
latencies to locate the old escape location were considered to
indicate spatial memory retention for the original location.
Spatial learning. Since the probe trials required the
mice to explore the new rotated box location, spatial learning
was regarded as the change of focus from the old to the new
escape box. The spatial learning index was calculated as the
ratio of the latency to explore the old location over the latency to
explore the new location of the escape box. The lower the index,
the worse was spatial learning for the new box.
Spatial learning effectiveness. Under challenging conditions in the probe trials mice were required to learn that the
old location of the escape no longer was correct and to locate the
new escape box among all other possible (false) box locations.
An index expressing spatial learning effectiveness for locating
the new escape box was calculated as the ratio of time the
animal spent exploring the new escape box over false boxes (old
escape box and false boxes). The higher the index, the better
was spatial learning for the new box.
STATISTICS
Power Calculation
We investigated 4 groups of 10 mice each with complete
cognition-like assessment and laboratory tests described
above. Only mice suitable (i.e., normal vision) for the
cognition-like assessment were used for the behavioral survey.
According to power calculations (PS software, version 2.1.31), a
sample size of 10 mice per group was required to identify a 20%
difference of cognitive performance between mouse strains for
80% study power (alpha-type I error probability of P < 0.05 for
a two sided test).
Statistical Analysis
Data analysis was carried out using the integrated, purposedesigned statistical software of the ANY-maze software
(version 4.3). As all animal data were not normally distributed
0.03
0.04
0.04
0.04
10.1 1.9
0.03 0.006
11.7 1.5
0.04 0.006
16.3 1.7
0.05 0.006
11.1 1.0
0.04 0.003
0.008
0.009
0.06
0.06
3.3 0.4
0.018 0.002
4.2 0.5
0.023 0.004
4.0 0.5
0.022 0.003
5.1 0.5
0.028 0.003
SE, standard error.
*Trend calculated by Kruskal–Wallis test.
**Differences between groups calculated by Mann–Whitney U-test.
Training data in Figure 1 (object 1) and Figure 2 (object 2)
showed as expected for all mice strains increasing time spent in
the two zones with exploration of the two objects during the
training trial after the habituation phase (nine trials).
Table II shows that the time spent exploring both stimuli in
the retention phase varied significantly across all mice strains.
More specifically, B6.TNF/ mice spent significantly less time
exploring objects in these tests as compared to B6.WT, whereas
B6.TNF-R1/ and B6.TNF-R2/ mice explored the objects
with moderate duration. These differences between mice
strains were not skewed by basic differences in overall explorative behavior (regardless of object exploration) since all mice
strains showed overall similar distance traveled and speed of
travel during the retention trial.
The preferential exploration of the novel object in the
retention phase indicated most successful learning and
retention for B6.TNF-R2/, B6.TNF-R1/, and B6.WT mice,
which was significantly higher than B6.TNF/ mice (Fig. 3).
WT (N ¼ 10),
mean SE
Object Recognition Memory in
Novel Object Recognition
TNF-R1/
(N ¼ 10),
mean SE
As TNF is implicated in metabolic deregulation such as
cachexia [Beutler et al., 1985] or obesity [Spiegelman and
Hotamisligil, 1993], we examined whether these mice showed
differences in weight. Mean age (58.4–78.1 days) and weight
(23.9–27.8 g) were similar between all four strains.
General motor activity was assessed under two conditions.
In a non-stressful setting, that is in home cage bedding, there
was no significant difference in locomotor activity across mice
strains except that B6.TNF/ mice performed poorer in
these tests as compared to B6.WT mice (Table I). Under more
stressful conditions, that is, under bright light in novel
surroundings during the open field test, there was a significant
variation in travel distances and speed across mice strains with
most prominent differences between B6.WT and B6.TNF-R1/
mice (P < 0.03; P < 0.04) (Table I). Since locomotor activity at
the beginning of the trials in the Novel Object Recognition Test
and the Barnes Maze showed no significant differences in
speed and distances traveled between the mice strains, it can
be assumed that the variation of cognition-like behavior is
not simply related to differences in basic locomotor activity
between the mice strains (data not shown).
Peripheral cytokine analyses showed that the mouse held
under SPF conditions expressed neither TNF nor any other
tested cytokine (IL-1-b, IL-6, IL-8, IL-10, IL-12) at a detectable
level.
TABLE I. Open Field Locomotor Activity
Locomotor Activity, Body Weight, and Cytokine Levels
TNF-R2/
(N ¼ 10),
mean SE
TNF/
(N ¼ 10),
man SE
RESULTS
Home cage condition
Total distance traveled (m)
Overall average speed (m/sec)
Open field condition (without habituation)
Total distance traveled (m)
Overall average speed (m/sec)
Trend*
P-value for
(tested with Kolmogorov–Smirnov test), only non-parametric
tests were used for all analyses. The main outcome parameters
of the standardized behavioral tests, such as retention memory
and learning indices are composite measure of single cognitionlike behavioral tests according to standardized test procedures. For comparisons of single and composite outcome
parameters of cognition-like behavioral tests between two
independent groups of mice (Tables I–III, Figs. 1–4) we used
the Mann–Whitney U-test and for group comparisons of >2
independent groups of mice, the Kruskal–Wallis test was
applied (Tables I–III) [Zar, 1984]. More specifically, the
significance of the variation in cognition-like behavior across
strains of gene-targeted B6.TNF and B6.WT mice was tested
using the Kruskal–Wallis. Analyzing the assumption that the
absence of TNF is detrimental for cognition-like behavior, we
compared single test parameters between B6.TNF/ and
B6.WT mice using Mann–Whitney U-test.
Group differences
TNF/ vs.WT mice**
TNF Deficiency and Cognition
1059
1060
Baune et al.
TABLE II. Single Results in the Novel Object Recognition Test
P-value for
Time (sec) explored
the objects
WT (N ¼ 10),
mean SE
TNF-R1/
(N ¼ 10),
mean SE
TNF-R2/
(N ¼ 10),
mean SE
TNF/
(N ¼ 10),
mean SE
Trend*
Group differences
TNF/ vs. WT
mice**
Retention
Old object (sec)
New object (sec)
13.4 3.2
18.0 5.4
8.8 2.4
13.5 4.1
5.6 2.5
9.6 4.4
4.3 0.9
2.2 0.7
0.04
0.01
0.005
0.01
SE, standard error.
*Trend calculated by Kruskal–Wallis test.
**Differences between groups calculated by Mann–Whitney U-test.
Spatial Memory and Learning
Performance in Barnes Maze
Spatial retention memory. Acquisition data of the
Barnes Maze demonstrated significant successful spatial
learning in all mice strains (Fig. 4). During the two probe
trials, all mice strains showed similar overall distance traveled
and speed of travel. In both probe trials, spatial retention
memory, demonstrated by short latencies to locate the old
‘‘known’’ escape box, showed no significant variations across
mice strains (Table III). While B6.TNF/ mice had a tendency
to perform poorer in spatial retention memory as compared to
B6.WT mice, this difference reached no statistical significance
(Table III). Moreover, B6.TNF-R1/ and B6.TNF-R2/
mice performed not significantly different from the other
mice strains.
Spatial learning. Figure 5 illustrates that all genetargeted mice strains had significantly poorer spatial learning
performance for the new escape box as compared to B6.WT
mice. More specifically, while B6.TNF/ mice showed the
worst spatial learning ability among all strains as compared to
B6.WT mice (Fig. 5), the spatial learning performance of
B6.TNF/ mice was not significantly poorer when compared
to B6.TNF-R1/ or B6.TNF-R2/ mice.
Learning effectiveness. Figure 6 demonstrates spatial
learning effectiveness for the new escape box comparing the
performances of B6.WT, B6.TNF-R1/ and B6.TNF-R2/
mice to B6.TNF/ mice that were expected to have a poor
learning effectiveness according to results on spatial learning
(Fig. 5). These results showed that B6.TNF/ mice demonstrated the poorest spatial learning effectiveness for the new
escape box as compared to B6.WT and B6.TNF-R1/ and
B6.TNFR2/ mice (Fig. 6). In addition, moderate performance
differences between the latter three mouse strains were not
significant.
TNF Specificity
Lymphotoxin-alpha (LT-a) as well as TNF signal through
TNF-R1 and TNF-R2 receptors [Probert et al., 2000]. In order
to show that the effect of TNF on cognitive function mediated
through TNF-R1 and TNF-R2 was not substantially biased by
LT-a signaling through the TNF receptors, we compared
cognitive function in B6.TNF-deficient mice to B6.LT-a
deficient mice. Figure 7 showed preferential object recognition
performance in the Novel Object Recognition test. While
B6.TNF-deficient mice had significantly worse object recognition and retention in this test as compared to both B6.LT-a
deficient mice and B6.WT mice, B6.WT and B6.LT-a deficient
mice showed no significant differences in this test. As a
conclusion, cognitive dysfunction observed in all tests is a
specific result of TNF deficiency and not (or to only a very minor
degree) due to LT-a deficiency.
TABLE III. Single Results on Spatial Learning and Memory{ in the Barnes Maze
P-value
Probe trial 1 (1808)
Latency for new escape box
(sec)
Latency for old escape box
(sec)
Time spent exploring new
box (sec)
Time spent exploring old
box (sec)
Time in false box areas (sec)
Probe trial 2 (908)
Latency for new escape box
(sec)
Latency for old escape box
(sec)
WT (N ¼ 10),
mean SE
TNF-R1/
(N ¼ 10),
mean SE
TNF-R2/
(N ¼ 10),
mean SE
TNF/
(N ¼ 10),
mean SE
Trend*
Group differences
TNF/ vs. WT
mice**
25.5 7.0
65.2 10.7
46.6 6.6
84.6 18.6
0.012
0.01
19.6 6.1
30.5 11.8
21.0 7.8
30.1 9.8
0.87
0.46
12.8 5.4
13.1 5.6
10.0 5.4
1.5 0.6
0.3
0.05
44.7 15.7
14.9 4.6
13.8 2.6
47.7 21.0
0.28
0.45
30.1 5.7
46.8 7.2
57.8 6.3
79.7 17.5
0.03
0.04
61.6 19.8
87.1 30.8
60.0 19.2
78.7 21.8
0.91
0.77
42.8 18.2
41.6 17.5
16.2 3.9
24.1 10.9
0.80
0.44
SE, standard error.
{
Retention memory for the (known) old escape box was considered as the tendency of the mice to explore the old escape box in the probe trial instead of
exploring the new (unknown) box location.
*P-value of trend calculated by Kruskal–Wallis test.
**P-value of differences between groups calculated by Mann–Whitney U-test.
TNF Deficiency and Cognition
Fig. 1. Learning curve for object 1 in the Novel Object Recognition test.
*Time spent with the object in the exploration zone during the training
period and without the object in the habituation period. Error bars denote
standard deviation. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
DISCUSSION
In this study we investigated effects of TNF deficiency on
cognitive function. The main result is that under noninflammatory immune conditions the expression of TNF
appeared to be essential for normal memory and learning
processes in adult mice. In addition, we found evidence that the
specific cognition-like effects of TNF were not modulated by
LT-a that transmits signals through the same TNF receptors.
Furthermore, undetectable levels of a range of peripheral
cytokines provide evidence for non-inflammatory conditions
of the experiments. Importantly, the results of the object
recognition test and the Barnes Maze tests were not skewed by
any relevant differences in speed or distance traveled between
mice strains as all mice strains showed similar values during
these tests (data not shown) as opposed to the results under
home cage and unchallenged condition as shown in Table I.
These findings indicate that B6.TNF/ mice were less active
under resting conditions than B6.WT mice, but they were
similarly active when challenged by the Nobel Object Recognition test and Barnes maze test.
Our findings add to the evidence for an involvement of TNF
in complex CNS functions such as learning and memory, here
with an emphasis on unchallenged physiological conditions in
the CNS. While previous research demonstrated that TNF
overexpression in rodents had negative effects on cognitive
function such as memory [Fiore et al., 1996; Aloe et al., 1999;
Matsumoto et al., 2002], on the contrary, our study showed that
TNF deficiency was related to poor memory and learning
processes in mice. Generally, studies reporting on the genetic
involvement of TNF with cognitive function are rare in the
Fig. 2. Learning curve for object 2 in the Novel Object Recognition test.
*Time spent with the object in the exploration zone during the training
period and without the object in the habituation period. Error bars denote
standard deviation. [Color figure can be viewed in the online issue, which is
available at www.interscience.wiley.com.]
1061
Fig. 3. Preferential object recognition in the Novel Object Recognition
Test. P values determined by Mann–Whitney U-test show significance levels
for each difference between WT, TNF-R1/, TNF-R2/ mice as compared to
TNF/ mice (reference); #a preference index, a ratio of the amount of time
spent exploring any one of the two items (training session) or the novel object
(retention session) over the total time spent exploring both objects, was used
to measure recognition memory: a preference index >1 was regarded as
successful learning and retention; error bars denote standard deviation.
literature. In support of our reported finding of a genetic
component of TNF in cognitive function, a recent study in
humans by this group showed a significant association between
the TNF-alpha-308 G–>A polymorphism and processing
speed under immunological unchallenged conditions [Baune
et al., in press].
More and more evidence emerges suggesting properties and
mechanisms of TNF which form the possible molecular and
cellular basis of TNF effects in the CNS. TNF is constitutively
expressed in the CNS, it appears to be involved in the
modulation of neuronal activities in the normal human brain
[Dunn et al., 1999; McCann et al., 2000] and it has been
suggested that the continual presence of TNF is required for
preservation of synaptic strengths at the excitatory synapse
[Beattie et al., 2002].
More specifically, TNF is involved in several processes
subserving cognition, such as synaptic scaling [Stellwagen
and Malenka, 2006] and changes in LTP altered by TNF as
well as in changes in neurotransmitter metabolism [Dunn
et al., 1999], modulation of neuronal and glial cell function
Fig. 4. Acquisition data of the Barnes Maze during the 4-day training
period. The decreasing latency to enter the escape box in sec shows learning
to find the escape box faster over time. Error bars denote standard deviation.
[Color figure can be viewed in the online issue, which is available at
www.interscience.wiley.com.]
1062
Baune et al.
Fig. 5. Spatial learning of gene-targeted TNF, TNF-R1, and TNF-R2
mice. P values determined by Mann–Whitney U-test show significance
levels for each difference between TNF/, TNF-R1/, TNF-R2/ mice as
compared to WT mice (reference); #the spatial learning index was calculated
as the ratio of the latency to explore the old location over the latency to
explore the new location of the escape box: the lower the index, the worse was
spatial learning for the new box. Error bars denote standard deviation.
[Griffin et al., 1998], and neuro-developmental processes
[Stellwagen and Malenka, 2006]. The impaired cognitive
function of TNF/ mice might be explained by morphological
and electrophysiological alterations in the CNS of these mice as
demonstrated in previous studies. A study by Golan et al.
[2004] demonstrates that pyramidal neurons within the
hippocampus of young TNF knockout mice displayed less
dendritic arborization compared to WT mice. However, it is
unknown so far, if this morphological difference remains in
adulthood as studied here. Moreover, in electrophysiological
studies, slices from TNF receptor knockout mice (both R1 and
R2) display impaired long-term depression (LTD), but normal
basal transmission and slightly reduced LTP [Albensi and
Mattson, 2000], both mechanisms potentially with negative
impact on cognitive function. Although slices prepared from
TNF/ mice demonstrated normal LTP or LTD, they did
however display impairment in homeostatic synaptic scaling
[Stellwagen and Malenka, 2006], which is another mechanism
suggested to serve memory function [Bains and Oliet, 2007;
Turrigiano, 2007].
Our results possibly reflect effects of TNF on neurodevelopment at an early stage since TNF deficient mice had no
exposure to TNF during brain development. However, it
requires further clarification if TNF effects on cognitive
function are due to an absence during certain stages of brain
development, such as early stages of neurodevelopment, or if
Fig. 6. Learning effectiveness of gene-targeted TNF, TNF-R1, and TNFR2 mice. P values determined by Mann–Whitney U-test show significance
levels for each difference between WT, TNF-R1/, TNF-R2/ mice as
compared to TNF/ mice (reference); #an index expressing spatial learning
effectiveness for locating the new escape box was calculated as the ratio
of time the animal spent exploring the new escape box over false boxes (old
escape box and false boxes): the higher the index, the better was spatial
learning for the new box. Error bars denote standard deviation.
continuous exposure of the brain to TNF even in the adult brain
is essential for maintenance of normal cognitive function. The
latter possibility is supported by a recent study suggesting that
the continual presence of TNF is required for preservation of
synaptic strengths at the excitatory synapse [Beattie et al.,
2002].
In this study, cognitive performance between B6.TNF-R1
and B6.TNF-R2 gene targeted mice, was not different despite
the previously reported receptor specific neuroprotective
[Bruce et al., 1996; Gary et al., 1998; Pradillo et al., 2005]
(mediated through TNF-R2) and neurodegenerative [Dawson
et al., 1996; Barone et al., 1997; Nawashiro et al., 1997; Lavine
et al., 1998; Yang et al., 1998] (mediated through TNF-R1)
effects in the CNS.
According to the literature on the differential neurodegenerative and neuroprotective effects of TNF receptor R1 and R2,
we expected better cognitive test results in B6.TNF-R1/ as
compared to B6.TNF-R2/ mice. This suggestion is supported
by a recent study that revealed differential actions of TNF-R1
and TNF-R2 signaling in adult hippocampal neurogenesis
identifying TNF-R1 as a negative regulator of neural progenitor proliferation in both the intact and the pathological brain
[Iosif et al., 2006]. Our results on the negative impact of the
deletion of both TNF receptors (R1 or R2) on cognitive function
suggest multiple functions of the TNF-receptors (R1 and R2)
rather than receptor-specific neuroprotective or neurotoxic
effects. Signaling through these receptors appeared not to
be exclusively either detrimental or neuroprotective and
therefore our results on TNF receptors are not in support of a
specific role of these TNF receptors in cognitive function.
Furthermore, both TNF-R1 and TNF-R2 receptors might have
the capacity to mediate TNF signals essential for cognitive
function in the absence of the other receptor, an assumption
requiring further clarification.
Although both TNF receptors (TNF-R1 and TNF-R2) play a
role in cognitive function, alternative explanations of TNF
effects on cognitive functioning are required since TNF
develops its effects through various mechanisms and pathways. Through its effects on AMPA receptor trafficking, TNF
may play roles in synaptic plasticity and modulating response
to neural injury [Beattie et al., 2002]. Under the condition of
permanent TNF deficiency as in our research, the chronic
Fig. 7. Preferential object recognition in the Novel Object Recognition
Test of B6.LT-alpha/, B6.TNF/ and B6.WT mice. P-value determined by
Mann–Whitney U-test shows significance levels for each difference between
WT, TNF-R1/, TNF-R2/ mice as compared to TNF/ mice (reference);
#
a preference index, a ratio of the amount of time spent exploring any one of
the two items (training session) or the novel object (retention session) over
the total time spent exploring both objects, was used to measure recognition
memory: a preference index >1 was regarded as successful learning and
retention; error bars denote standard deviation.
TNF Deficiency and Cognition
lacking of this repairing effect might have contributed to
cognitive dysfunction as reported here. Furthermore, recent
research demonstrated a range of effects of TNF on CNS
function, such as alterations of synaptic scaling and LTP in
the dorsal horn of the spinal cord by TNF as well as TNFinduced changes in neurotransmitter metabolism, and neurodevelopmental processes [Stellwagen and Malenka, 2006].
How these TNF-related CNS functions and the permanent
absence of TNF like in our research specifically impact on
cognitive function such as memory and learning requires
further clarification.
Given the presented results and the complex interactions of
TNF within the CNS, TNF appears to be an interesting
candidate gene for association studies in neuropsychiatric
disorders involving cognitive dysfunction (i.e., Alzheimer’s
disease) [Rothwell and Loddick, 2002; Ransohoff and Benveniste, 2006] or depression [Hickie and Lloyd, 1995; Kronfol and
Remick, 2000; Capuron and Dantzer, 2003; Raison et al., 2006;
Irwin and Miller, 2007]. Moreover, TNF might be an ideal
target for therapeutic interventions in cognitive dysfunction of
Alzheimer’s disease [Tobinick et al., 2006; Medeiros et al.,
2007].
SUMMARY
We have investigated the effects of deficiency of TNF (TNF/)
and its main receptors (TNF-R1/ and TNF-R2/) on
cognitive function such as memory and learning in genetargeted mice. Our results indicate that TNF is absolutely
essential for memory functions and learning processes
whereas each of the two main TNF receptors exert similar
moderately reducing effects on cognitive function. Thus, TNF
and its two main receptors display interesting candidate genes
for cognitive function. Translational research is required to
investigate associations between genetic variants of TNF and
cognitive function in human healthy samples and also in
clinical samples of depression or Alzheimer’s disease since both
psychiatric disorders are characterized by a range of cognitive
dysfunctions.
ACKNOWLEDGMENTS
The study was funded by an internal grant of James Cook
University.
REFERENCES
Aggarwal BB, Samanta A, Feldmann M. 2000. TNF receptors. In:
Oppenheim LL, Feldmann M, Hirano T, Vilcek J, Nicola N, editors.
Cytokine reference: A compendium of cytokines and other mediators of
host defense (Vol. 1 and 2). San Diego, CA: Academic Press. pp 1619–1632.
Albensi BC, Mattson MP. 2000. Evidence for the involvement of TNF and
NF-kappaB in hippocampal synaptic plasticity. Synapse 35(2):151–159.
Aloe L, Properzi F, Probert L, Akassoglou K, Kassiotis G, Micera A, Fiore M.
1999. Learning abilities, NGF and BDNF brain levels in two lines of
TNF-alpha transgenic mice, one characterized by neurological disorders, the other phenotypically normal. Brain Res 840(1–2):125–137.
Bains JS, Oliet SH. 2007. Glia: They make your memories stick. Trends
Neurosci 30(8):417–424.
Barone FC, Arvin B, White RF, Miller A, Webb CL, Willette RN, Lysko PG,
Feuerstein GZ. 1997. Tumor necrosis factor-alpha. A mediator of focal
ischemic brain injury. Stroke 28:1233–1244.
Baune BT, Ponath G, Golledge J, Varga G, Rothermundt M, Berger K. 2007.
Association between IL-8 cytokine and cognitive performance in an
elderly general population—The MEMO-study. Neurobiol Aging (in
press). DOI: 10.1016/j.neurobiolaging.2006.12.003
Baune BT, Ponath G, Rothermundt M, Riess O, Funke H, Berger K. 2008.
Association between genetic variants of IL-1b, IL-6 and TNF-a cytokines
and cognitive performance in the elderly general population of the
MEMO-study. Psychoneuroendocrinology 33:68–76.
1063
Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow
M, Beattie MS, Malenka RC. 2002. Control of synaptic strength by glial
TNFalpha. Science 295(5563):2282–2285.
Bernardino L, Xapelli S, Silva AP, Jakobsen B, Poulsen FR, Oliveira CR,
Vezzani A, Malva JO, Zimmer J. 2005. Modulator effects of interleukin 1beta and tumor necrosis factor-alpha on AMPA-induced neurotoxicity in
mouse organotypic hippocampal slice cultures. J Neurosci 25:6734–
6744.
Beutler BA, Milsark IW, Cerami A. 1985. Cachectin/tumor necrosis factor:
Production, distribution, and metabolic fate in vivo. J Immunol
135(6):3972–3977.
Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK,
Holtsberg FW, Mattson MP. 1996. Altered neuronal and microglial
responses to excitotoxic and ischemic brain injury in mice lacking TNF
receptors. Nat Med 2:788–794.
Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P,
Pedersen BK. 1999. A high plasma concentration of TNF-alpha is
associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci
54(7):M357–M364.
Capuron L, Dantzer R. 2003. Cytokines and depression: The need for a new
paradigm. Brain Behav Immun 17 (Suppl 1):S119–S124.
Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. 1995. FADD, a novel
death domain-containing protein, interacts with the death domain of Fas
and initiates apoptosis. Cell 81:505–512.
Dawson DA, Martin D, Hallenbeck JM. 1996. Inhibition of tumor necrosis
factor-alpha reduces focal cerebral ischemic injury in the spontaneously
hypertensive rat. Neurosci Lett 218:41–44.
Diem R, Meyer R, Weishaupt JH, Bahr M. 2001. Reduction of potassium
currents and phosphatidylinositol 3-kinase-dependent AKT phosphorylation by tumor necrosis factor-(alpha) rescues axotomized retinal
ganglion cells from retrograde cell death in vivo. J Neurosci 21:2058–
2066.
Dunn AJ, Wang J, Ando T. 1999. Effects of cytokines on cerebral
neurotransmission. Comparison with the effects of stress. Adv Exp
Med Biol 461:117–127.
Erickson SL, de Sauvage FJ, Kikly K, Carver-Moore K, Pitts-Meek S, Gillett
N, Sheehan KC, Schreiber RD, Goeddel DV, Moore MW. 1994. Decreased
sensitivity to tumour-necrosis factor but normal T-cell development in
TNF receptor-2-deficient mice. Nature 372(6506):560–563.
Fiore M, Probert L, Kollias G, Akassoglou K, Alleva E, Aloe L. 1996.
Neurobehavioral alterations in developing transgenic mice expressing
TNF-alpha in the brain. Brain Behav Immun 10(2):126–138.
Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U.
2002. Neurodegenerative and neuroprotective effects of tumor necrosis
factor (TNF) in retinal ischemia: Opposite roles of TNF receptor 1 and
TNF receptor 2. J Neurosci 22:RC216.
Gary DS, Bruce-Keller AJ, Kindy MS, Mattson MP. 1998. Ischemic and
excitotoxic brain injury is enhanced in mice lacking the p55 tumor
necrosis factor receptor. J Cereb Blood Flow Metab 18:1283–1287.
Golan H, Levav T, Mendelsohn A, Huleihel M. 2004. Involvement of tumor
necrosis factor alpha in hippocampal development and function. Cereb
Cortex 14(1):97–105.
Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham
DI, Roberts GW, Mrak RE. 1998. Glial-neuronal interactions in
Alzheimer’s disease: The potential role of a ‘cytokine cycle’ in disease
progression. Brain Pathol 8(1):65–72.
Hallenbeck JM. 2002. The many faces of tumor necrosis factor in stroke. Nat
Med 8:1363–1368.
Hickie I, Lloyd A. 1995. Are cytokines associated with neuropsychiatric
syndromes in humans? Int J Immunopharmacol 17(8):677–683.
Holocomb LA, Girdon MN, Jantzen P, Hasiao K, Duff K, Morgan D. 1999.
Behavioral changes in transgenic mice expressing both amyloid
precusor protein and presenilin-1 mutations: Lack of association with
amyloid deposits. Behav Genet 29:177–185.
Hopkins SJ, Rothwell NJ. 1995. Cytokines and the nervous system. I:
Expression and recognition. Trends Neurosci 18(2):83–88.
Hsu H, Xiong J, Goeddel DV. 1995. The TNF receptor 1-associated protein
TRADD signals cell death and NF-kappa B activation. Cell 81:495–
504.
Hsu H, Shu HB, Pan MG, Goeddel DV. 1996. TRADD-TRAF2 and
RADD-FADD interactions define two distinct TNF receptor 1 signal
transduction pathways. Cell 84:299–308.
1064
Baune et al.
Iosif RE, Ekdahl CT, Ahlenius H, Pronk CJ, Bonde S, Kokaia Z, Jacobsen SE,
Lindvall O. 2006. Tumor necrosis factor receptor 1 is a negative regulator
of progenitor proliferation in adult hippocampal neurogenesis.
J Neurosci 26(38):9703–9712.
Irwin MR, Miller AH. 2007. Depressive disorders and immunity: 20 years of
progress and discovery. Brain Behav Immun 21(4):374–383.
Kohno T, Brewer MT, Baker SL, Schwartz PE, King MW, Hale KK, Squires
CH, Thompson RC, Vannice JL. 1990. A second tumor necrosis factor
receptor gene product can shed a naturally occurring tumor necrosis
factor inhibitor. Proc Natl Acad Sci USA 87:8331–8335.
Korner H, Cook M, Riminton DS, Lemckert FA, Hoek RM, Ledermann B,
Kontgen F, Fazekas de St Groth B, Sedgwick JD. 1997. Distinct roles for
lymphotoxin-alpha and tumor necrosis factor in organogenesis and
spatial organization of lymphoid tissue. Eur J Immunol 27(10):2600–
2609.
Kronfol Z, Remick DG. 2000. Cytokines and the brain: Implications for
clinical psychiatry. Am J Psychiatry 157(5):683–694.
Lavine SD, Hofman FM, Zlokovic BV. 1998. Circulating antibody against
tumor necrosis factor-alpha protects rat brain from reperfusion injury.
J Cereb Blood Flow Metab 18:52–58.
Liston P, Roy N, Tamai K, Lefebvre C, Baird S, Cherton-Horvat G, Farahani
R, McLean M, Ikeda JE, MacKenzie A, et al. 1996. Suppression of
apoptosis in mammalian cells by NAIP and a related family of IAP genes.
Nature 379:349–353.
Matsumoto Y, Watanabe S, Suh YH, Yamamoto T. 2002. Effects of
intrahippocampal CT105, a carboxyl terminal fragment of beta-amyloid
precursor protein, alone/with inflammatory cytokines on working
memory in rats. J Neurochem 82(2):234–239.
McCann SM, Kimura M, Karanth S, Yu WH, Mastronardi CA, Rettori V.
2000. The mechanism of action of cytokines to control the release of
hypothalamic and pituitary hormones in infection. Ann NY Acad Sci
917:4–18.
McLay RN, Freeman SM, Zadina JE. 1998. Chronic corticosterone impairs
memory performance in the Barnes maze. Physiol Behav 63(5):933–937.
Raison CL, Capuron L, Miller AH. 2006. Cytokines sing the blues:
Inflammation and the pathogenesis of depression. Trends Immunol
27(1):24–31.
Ransohoff RM, Benveniste EN, editors. 2006. Cytokines and the CNS, 2nd
edition. New York: Taylor & Francis Group.
Rothwell NJ. 1999. Annual review prize lecture cytokines—Killers in the
brain? J Physiol 514:3–17.
Rothwell NJ, Hopkins SJ. 1995. Cytokines and the nervous system II:
Actions and mechanisms of action. Trends Neurosci 18(3):130–136.
Rothwell NJ, Loddick S, editors. 2002. Immune and inflammatory responses
in the nervous system, 2nd edition. New York: Oxford University Press.
Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC. 1997. The c-IAP-1
and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J
16:6914–6925.
Saha RN, Pahan K. 2003. Tumor necrosis factor-alpha at the crossroads of
neuronal life and death during HIV-associated dementia. J Neurochem
86(5):1057–1071.
Schwartz M, Solomon A, Lavie V, Ben-Bassat S, Belkin M, Cohen A. 1991.
Tumor necrosis factor facilitates regeneration of injured central nervous
system axons. Brain Res 545(1–2):334–338.
Schwartz M, Sivron T, Eitan S, Hirschberg DL, Lotan M, Elman-Faber A.
1994. Cytokines and cytokine-related substances regulating glial cell
response to injury of the central nervous system. Prog Brain Res 103:
331–341.
Sean Riminton D, Korner H, Strickland DH, Lemckert FA, Pollard JD,
Sedgwick JD. 1998. Challenging cytokine redundancy: Inflammatory
cell movement and clinical course of experimental autoimmune
encephalomyelitis are normal in lymphotoxin-deficient, but not tumor
necrosis factor-deficient, mice. J Exp Med 187(9):1517–1528.
Shipno K, Kikuchi S, Moriwaka F, Tashiro K. 1999. Protective effects of the
TNF-ceramide pathway against glutamte neurotoxicity on cultured
mesencephalic neurons. Brain Res 819:170–173.
Simen BB, Duman CH, Simen AA, Duman RS. 2006. TNFalpha signaling in
depression and anxiety: Behavioral consequences of individual receptor
targeting. Biol Psychiatry 59(9):775–785.
Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL,
Dafre AL, Di Giunta G, Figueiredo CP, Takahashi RN, et al. 2007.
Connecting TNF-alpha signaling pathways to iNOS expression in a
mouse model of Alzheimer’s disease: Relevance for the behavioral and
synaptic deficits induced by amyloid beta protein. J Neurosci 27(20):
5394–5404.
Spiegelman BM, Hotamisligil GS. 1993. Through thick and thin: Wasting,
obesity, and TNF alpha. Cell 73(4):625–627.
Nawashiro H, Martin D, Hallenbeck JM. 1997. Inhibition of tumor necrosis
factor and amelioration of brain infarction in mice. J Cereb Blood Flow
Metab 17:229–232.
Tang YP, Wang H, Feng R, Kyin M, Tsien JZ. 2001. Differential effects of
enrichment on learning and memory function in NR2B transgenic mice.
Neuropharmacology 41(6):779–790.
Nophar Y, Kemper O, Brakebusch C, Englemann H, Zwang R, Aderka D,
Holtmann H, Wallach D. 1990. Soluble forms of tumor necrosis factor
receptors (TNF-Rs). The cDNA for the type I TNF-R, cloned using amino
acid sequence data of its soluble form, encodes both the cell surface and a
soluble form of the receptor. EMBO J 9:3269–3278.
Tartaglia LA, Ayres TM, Wong GH, Goeddel DV. 1993. A novel domain
within the 55 kd TNF receptor signals cell death. Cell 74:845–853.
Owens T, Wekerle H, Antel J. 2001. Genetic models for CNS inflammation.
Nat Med 7:161–166.
Peschon JJ, Torrance DS, Stocking KL, Glaccum MB, Otten C, Willis CR,
Charrier K, Morrissey PJ, Ware CB, Mohler KM. 1998. TNF receptordeficient mice reveal divergent roles for p55 and p75 in several models of
inflammation. J Immunol 160(2):943–952.
Pollmacher T, Haack M, Schuld A, Reichenberg A, Yirmiya R. 2002. Low
levels of circulating inflammatory cytokines—Do they affect human
brain functions? Brain Behav Immun 16(5):525–532.
Pradillo JM, Romera C, Hurtado O, Cardenas A, Moro MA, Leza JC, Davalos
A, Lorenzo P, Lizasoain I. 2005. TNFR1 upregulation mediates tolerance
after brain ischemic preconditioning. J Cereb Blood Flow Metab 25:193–
203.
Probert L, Eugster HP, Akassoglou K, Bauer J, Frei K, Lassmann H,
Fontana A. 2000. TNFR1 signalling is critical for the development of
demyelination and the limitation of T-cell responses during immunemediated CNS disease. Brain 123(Pt 10):2005–2019.
Stellwagen D, Malenka RC. 2006. Synaptic scaling mediated by glial
TNF-alpha. Nature 440(7087):1054–1059.
Tobinick E, Gross H, Weinberger A, Cohen H. 2006. TNF-alpha modulation for treatment of Alzheimer’s disease: A 6-month pilot study.
MedGenMed 8(2):25.
Tonelli LH, Postolache TT. 2005. Tumor necrosis factor alpha, interleukin-1
beta, interleukin-6 and major histocompatibility complex molecules in
the normal brain and after peripheral immune challenge. Neurol Res
27(7):679–684.
Turrigiano G. 2007. Homeostatic signaling: The positive side of negative
feedback. Curr Opin Neurobiol 17(3):318–324.
Wall PM, Messier C. 2002. Infralimbic kappa opioid and muscarinic M1
receptor interactions in the concurrent modulation of anxiety and
memory. Psychopharmacology (Berl) 160(3):233–244.
Wilhelm P, Ritter U, Labbow S, Donhauser N, Rollinghoff M, Bogdan C,
Korner H. 2001. Rapidly fatal leishmaniasis in resistant C57BL/6 mice
lacking TNF. J Immunol 166(6):4012–4019.
Yang GY, Gong C, Qin Z, Ye W, Mao Y, Bertz AL. 1998. Inhibition of
TNFalpha attenuates infarct volume and ICAM-1 expression in
ischemic mouse brain. Neuroreport 9:2131–2134.
Zar JH. 1984. Biostatistical analysis. New Jersey: Prentice Hall. 178 p.
Документ
Категория
Без категории
Просмотров
2
Размер файла
209 Кб
Теги
dysfunction, deficiency, mice, receptors, cognitive, tnf
1/--страниц
Пожаловаться на содержимое документа