Review
Evidence for a cytokine model of cognitive function
J. McAfoose, B.T. Baune *
Psychiatry and Psychiatric Neuroscience, School of Medicine and Dentistry, James Cook University, Townsville, Queensland 4811, Australia
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
2. Molecular and cellular aspects of cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
2.1. Memory consolidation and synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
2.2. Hebbian synaptic plasticity ­ LTP and LTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
2.3. Synaptic scaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
2.4. Neurogenesis and memory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
3. Cytokine model of cognition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
3.1. IL-1 influences cognitive function by affecting long-term potentiation and possibly neurogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . 357
3.2. IL-6 impacts cognitive function via effects on neurogenesis and synaptic plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
3.3. TNF alpha influences cognitive function through direct effects on LTP and synaptic scaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
3.4. Other potential mechanisms by which cytokines might mediate cognitive processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
3.5. Other cytokines potentially influencing cognitive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
3.5.1. Alpha1-antichymotrypsin (ACT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
3.6. Interferon-gamma (IFN-gamma) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
3.7. Interleukin-2 (IL-2). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
3.8. Cytokine signalling pathways in the injured brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 362
4. Limitations and future research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
5. Clinical implications and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 364
Neuroscience and Biobehavioral Reviews 33 (2009) 355­366
A R T I C L E I N F O
Article history:
Received 1 July 2008
Received in revised form 10 October 2008
Accepted 11 October 2008
Keywords:
Cytokines
Cognition
CNS
TNF
IL-6
IL-1beta
IFNg
Alpha(1)-antichymotrypsin
A B S T R A C T
Aiming at a formulation of a cytokine model of cognitive function under immunologically unchallenged
physiological conditions, this article reviews the cytokine biology in the central nervous system (CNS)
and recent developments in normal cytokine functions within the CNS that subserve cognitive processes.
Currently available evidence shows that the cytokines IL-1b, IL-6 and TNF-a play a role in complex
cognitive processes at the molecular level, such as synaptic plasticity, neurogenesis, as well as
neuromodulation. Such findings provide evidence for a cytokine model of cognitive function, which
shows that cytokines play an intimate role in the molecular and cellular mechanisms subserving learning,
memory and cognition under physiological conditions. These cytokine-mediated cognitive processes
have implications in the long-term development and pathogenesis of specific neuropsychiatric disorders
such as major depression and dementia. The identification of this central role of cytokines in various brain
activities during health provides greater insight into normal brain functions, especially synaptic
plasticity, memory and cognition, and facilitates the understanding of specific biological mechanisms
involved in neuropsychiatric diseases, such as dementia and depression. In order to extend the suggested
cytokine model of cognitive function onto other members of the cytokine family, future research is
required to investigate the physiological effects of other cytokines such as interferon-gamma (IFNg),
alpha(1)-antichymotrypsin and IL-2 on cognitive function at the molecular level under immunologically
unchallenged conditions.
ß 2008 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +61 7 4781 6731; fax: +61 7 4781 6841.
E-mail address: bernhard.baune@jcu.edu.au (B.T. Baune).
Contents lists available at ScienceDirect
Neuroscience and Biobehavioral Reviews
journal homepage: www.elsevier.com/locate/neubiorev
0149-7634/$ ­ see front matter ß 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2008.10.005
1. Introduction
The interactions between the immune and central nervous
systems (CNS) in pathological states such as multiple sclerosis and
depression have long been under investigation. In recent years, the
discovery of multiple functions of cytokines in the central nervous
system suggests that cytokines play a central role in complex CNS
functions such as cognition (Hopkins and Rothwell, 1995;
Pollmacher et al., 2002; Rothwell, 1999; Rothwell and Hopkins,
1995; Wilson et al., 2002). Most notably, the over-expression of
cytokines has been associated with numerous pathological states
(both within the central and peripheral nervous system), such as
infection (viral, bacterial and fungal), autoimmune disease (i.e.
multiple sclerosis), stroke, trauma, neurodegenerative disease (i.e.
Alzheimer's disease (AD) and other dementias) (Ransohoff and
Benveniste, 2006; Rojo et al., 2008; Rothwell and Loddick, 2002;
Shaftel et al., 2008; Viviani et al., 2004) and in neuropsychiatric
disorders, such as depression (Anisman et al., 2008; Capuron and
Dantzer, 2003; Dantzer et al., 2008; Irwin and Miller, 2007; Kronfol
and Remick, 2000; Raison et al., 2006). More specifically, some
cytokines, such as interleukin 1beta (IL-1-beta), interleukin 6 (IL-6)
and tumor necrosis factor (TNF) have been associated with
cognitive decline and dementia in several cross-sectional and
prospective population studies (Dik et al., 2005; Holmes et al.,
2003; Schmidt et al., 2002; Wilson et al., 2002). In addition,
cytokines, such as TNF and IL-1-beta have been related to
Alzheimer's disease in clinical cohorts (Dik et al., 2005; Holmes
et al., 2003).
It is now believed that cytokine-mediated pathophysiological
processes underlie the cognitive impairments associated with
several neuropsychiatric diseases, making cytokines ideal targets
for therapeutic intervention (Reichenberg et al., 2001; Tobinick,
2007; Tweedie et al., 2007; Wilson et al., 2002). Despite these
pathological implications (Bitsch et al., 2000; He et al., 2007),
cytokines have also been shown to exert physiological (Blatteis,
1990; Sei et al., 1995; Vitkovic et al., 2000a) and even
neuroprotective (Pan and Kastin, 2001; Schwartz et al., 1991,
1994) functions.
Research by this group suggests that in healthy elderly humans
cytokines, in particular interleukin 8, under physiological conditions,
are possibly involved in cognitive processes such as memory,
perceptual speed and motor function (Baune et al., 2008a).
Moreover, this group recently reported the associations between
genetic variants of cytokines (IL-1beta, IL-6 and TNF) and cognitive
function in healthy elderly humans in the general population
(Baune et al., 2008b). More specifically, the results suggest that
genetic variants of TNF may have protective effects in cognitive
function such as perceptual speed (Baune et al., 2008b). In an
animal model of cytokine-mediated cognitive function such as
memory and learning, we were able to demonstrate that the
presence of TNF under immunologically non-challenged conditions
is essential for normal functions of memory and learning
(Baune et al., 2008). This research linking complex cognitive
phenotypes and cytokine effects in the CNS is well based on
previous evidence to suggest that cytokines play a role in normal
CNS function at a cellular and molecular level (see Jankowsky and
Patterson, 1999 for review). For instance, during health both IL-1
and TNF have been shown to act as neuromodulators, as well as,
pro-inflammatory factors (Blatteis, 1990; Sei et al., 1995; Vitkovic
et al., 2000a,b).
Although these detrimental effects on cognitive function in
both over-expressing and cytokine deficient models suggest that
cytokines play an important physiological role in the CNS at the
molecular and cognitive level, it still remains to be fully understood
as to how cytokines participate in the molecular and cellular
mechanisms subserving complex CNS functions such as learning,
memory and cognition. Interestingly, growing evidence suggests
that in particular the cytokines IL-1, IL-6 and TNF are involved in
the molecular and cellular mechanisms subserving complex
cognitive processes (Pickering and O'Connor, 2007; Vitkovic
et al., 2000b; Viviani et al., 2007). While direct and indirect
evidences show that IL-1, IL-6 and TNF may play a major role in
synaptic plasticity, long-term potentiation (LTP), neurogenesis and
memory consolidation, the evidence for involvement with
cognitive function is less conclusive for other cytokines such as
interferon-gamma (IFNg) (Baron et al., 2008), alpha(1)-antichymotrypsin
(ACT) (Dik et al., 2005; McIlroy et al., 2000; Nilsson
et al., 2004) and IL-2 (Beck et al., 2002, 2005a,b).
In this review, we propose a cytokine model of cognitive
function during health under immunologically unchallenged
conditions. Aiming to establish an improved understanding
of cytokine-mediated cognitive function during physiological
conditions, current scientific literature on cytokine biology and
their related activities within the CNS during healthy immunologically
unchallenged conditions was reviewed. In particular,
this review primarily concentrates on the cytokines IL-1, IL-6 and
TNF-a as these cytokines have been shown to be involved in the
molecular mechanisms underlying learning and memory consolidation.
In addition, we also review other cytokines, especially
IFNg, ACT and IL-2 which have significant implications in
neurogenesis and possibly in complex cognitive processes such
as learning and memory consolidation, although their potential
molecular mechanisms in learning and memory are not sufficiently
studied at this stage.
This approach allows the distinction between cytokines
providing conclusive evidence for a cytokine model of cognitive
function and those cytokines suggestive of their involvement in
higher cognitive function under physiological healthy conditions.
It is intended that the models of physiological cytokine activities
and properties as described in this review propose a cytokinemediated
model of cognitive function that would provide further
understanding into pathological consequences of cytokines during
disease. Finally, this review discusses current limitations, clinical
implications and future research of a cytokine model of cognitive
function.
2. Molecular and cellular aspects of cognition
Cognition often refers to a collection of cognitive processes,
such as attention, executive function, learning and memory,
consciousness, and language. Of these cognitive processes, there
has been particular interest in recent years on the involvement of
cytokines in learning and memory processes. More specifically,
this area of research has largely directed its efforts at clarifying the
role that cytokines play in hippocampal-dependent learning and
memory; i.e., spatial memory, object recognition and contextual
fear conditioning. The reasons for a focus on learning and memory
processes in this review are that, firstly the neuronal mechanisms
underlying higher cognitive functions such attention, executive
function, consciousness and language and their relationship with
cytokines remain poorly understood and secondly these other
higher cognitive processes appear to rely heavily on learning and
memory processes. Moreover, since the hippocampal formation
appears to play a major role in memory consolidation, an emphasis
was placed, in this review, on how cytokines participate in the well
known and extensively studied molecular and cellular processes
thought to be subserving memory formation.
As a consequence, in this review we firstly focus on the
involvement of cytokines in these molecular and cellular processes
and secondly we emphasize on the involvement of cytokines in
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366356
learning and memory processes as the basis for the proposed
cytokine model of cognitive function. A brief overview will be
given on the molecular processes of memory consolidation and
synaptic plasticity before evaluating and discussing the involvement
of a number of cytokines in these molecular processes.
2.1. Memory consolidation and synaptic plasticity
In brief, `memory consolidation' is the neuropsychological
mechanism and/or structural changes within the brain that allows
memories to be stored more permanently. Supported by neuroimaging
results (i.e. Bosshardt et al., 2005; Lepage et al., 1998) it is
now widely believed that activation of the hippocampal formation
is associated with memory consolidation; at least for some forms
of memory. In concurrence with these findings, some (Buckner,
2003; Knowlton and Fanselow, 1998; Meeter and Murre, 2005;
Nadel and Moscovitch, 1997) have suggested that memory
consolidation is collectively contingent on hippocampal/entrorhinal
and cortical interactions.
Although the exact neurobiological mechanisms subserving
memory consolidation remain to be fully understood, three
proposed cellular/molecular mechanisms have received wide
acceptance; Hebbian plasticity (Malenka and Bear, 2004), synaptic
scaling (Burrone and Murthy, 2003; Perez-Otano and Ehlers, 2005;
Turrigiano, 2007), and adult neurogenesis (Bruel-Jungerman et al.,
2007a,b; Drapeau et al., 2007). Although it was widely believed
that these mechanisms were independent of each other, there is
now evidence showing that these different forms of synaptic
plasticity are functionally linked and act as associate partners
during the formation and retention of memories (see BruelJungerman
et al., 2007a for further details).
2.2. Hebbian synaptic plasticity ­ LTP and LTD
One of the earliest and most widely accepted neurobiological
theories as to how memories are consolidated is Hebbian synaptic
plasticity. According to this theory a synapse will be strengthened
if the pre-synaptic neuron is active while the post-synaptic neuron
is firing; a process called Hebbian modification (Hebb, 1949).
During repeated synaptic excitations of a single synapse (sensitization)
or multiple synapses simultaneously (conditioning),
neurons become `potentiated' or highly responsive, for minutes,
days, or weeks. This has lead to the suggestion that long-term
potentiation and long-term depression (LTD), which is, respectively,
the strengthening or weakening of synaptic connectivity
due to stimulation, is the underlying cellular/molecular mechanism
subserving memory consolidation (Lynch, 2000; Lynch et al.,
2007; Lynch, 2004; Ziemann et al., 2004). In support of this notion,
research has shown that (1) the presence of LTP and LTD is widely
distributed throughout the mammalian brain, especially within
the hippocampus, (2) learning modifies subsequent induction of
both LTP and LTD and (4) inhibition of LTP and LTD impairs
memory (Lynch et al., 2007; Lynch, 2004; Malenka and Bear, 2004;
Ziemann et al., 2004).
2.3. Synaptic scaling
Despite wide acceptance for Hebbian synaptic plasticity, this
form of plasticity operates via positive feedback mechanisms that,
if left unchecked, tend to destabilize neuronal networks over time
(Perez-Otano and Ehlers, 2005; Turrigiano, 1999, 2007). In order to
maintain synaptic strength and plasticity, Hebbian plasticity
requires the regulation of synapse-specific LTP and LTD at both
the cell-wide and network level (Abbott and Nelson, 2000). A nonHebbian
form of synaptic plasticity, called homeostatic synaptic
scaling, appears to serve this function. During prolonged periods of
inactivity or hyperactivity, homeostatic synaptic scaling stabilizes
the activity of neurons and networks (Abbott and Nelson, 2000;
Burrone and Murthy, 2003; Echegoyen et al., 2007; Perez-Otano
and Ehlers, 2005; Turrigiano, 2007), thus facilitating Hebbian
synaptic plasticity, and possibly memory consolidation (Renart
et al., 2003).
2.4. Neurogenesis and memory
There is also considerable evidence to suggest that adult
neurogenesis plays an important role in memory consolidation,
and hippocampal-dependent learning (Bruel-Jungerman et al.,
2006, 2007a,b; Drapeau et al., 2007; Saxe et al., 2006; Snyder et al.,
2001). For instance, research by Dupret et al. (2007), suggests that
spatial learning involves learning-induced regulation of new
hippocampal neurons, in which both the removal (i.e. apoptosis)
and addition (neurogenesis) of hippocampal neurons contribute to
memory formation. However, research by Shors et al. (2002) and
Saxe et al. (2007), suggests that neurogenesis may be associated
with some forms of hippocampal-dependent memory but not
others. The exact mechanisms by which neurogenesis facilitates
memory formation remains to be fully understood. Moreover,
future research is also needed to clarify the relationship between
neurogenesis and both Hebbian and non-Hebbian forms of
synaptic plasticity.
3. Cytokine model of cognition
Interestingly, both the over-expression and absence of cytokines
have been shown to directly influence hippocampaldependent
forms of memory and various forms of synaptic
plasticity. Although the exact mechanisms as to how cytokines
participate in the molecular and cellular processes thought to be
subserving memory formation remains to be fully understood,
significant advances have been made in elucidating these
cytokine-mediated molecular and cellular processes. This section
will therefore concentrate on what is known about cytokinemediated
neuronal plasticity and how these processes might
influence memory and cognition. In particular, this section will
focus on IL-1b, TNFa and IL-6, which have been the subject of
extensive scientific investigation in this context. In addition, the
potential involvement of other cytokines such as IFNg, ACT and IL-
2 are evaluated and discussed in this context. Other possible
mechanisms as to how cytokines might influence cognitive
processes will also be given based on the known biological
properties of cytokines. Moreover, for the sake of clarity, a brief
introduction will be given on each cytokine and their associated
receptors.
3.1. IL-1 influences cognitive function by affecting long-term
potentiation and possibly neurogenesis
The IL-1 family of cytokines is a growing cytokine family, which
hitherto consists of the following cytokines, IL-1a (IL-1F1), IL-1b
(IL-1F2), IL-1 receptor antagonist (IL-1ra or IL-1F3), IL-18 (IL-1F4)
and IL-1F5-10. IL-1a and IL-1b display high sequence homology,
and both exist as inactive forms (pro-IL-1a and pro-IL-1b) until
they are cleaved by calpain and caspase-1, respectively. Once
cleaved, biologically activate IL-1a remains intracellular, whereas,
IL-1b is secreted by a non-classical pathway. To date, two
membrane-bound IL-1 receptors, type 1 (IL-1 R1) and type 2
(IL-1 R2), have been shown to bind IL-1a, IL-1b and IL-1ra.
Although, IL-1a and IL-1b bind to both receptors, evidence
suggests that IL-1 R1 mediates all of the responses of IL-1, whereas,
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366 357
IL-1 R2 appears to have no signalling properties (Colotta et al.,
1993, 1994). It has also been shown that IL-1 R1 has a higher
binding affinity for IL-1ra then both IL-1a and IL-1b, whereas, IL-1
R2 displays a higher binding affinity for IL-1b than IL-1a. Such
binding and receptor properties allow IL-1ra to act strongly as an
IL-1 antagonist. Moreover, since IL-1 R2 lacks signalling properties
and has a high binding affinity for IL-1b, IL-1 R2 is believed to
regulate IL-1 activity, especially IL-1b, by functioning as a decoy
receptor (Colotta et al., 1993, 1994; Re et al., 1996). Both IL-1 R1
and IL-1 R2 can exist as soluble receptors after shedding. Although
both soluble forms were originally believed to act antagonistically
by sequestering biologically active and pro-IL-1, it is now believed
that soluble IL-1 R1 (sIL-1 R1) can initiate signal transduction by
binding to IL-1R accessory protein (Allan et al., 2005). Although
the exact role in which these signalling and antagonistic mechanisms
might play in central nervous system function remains to be
fully understood, one possibility is neuromodulation or synaptic
plasticity.
Previous research has suggested that IL-1b can modulate
synaptic transmission in the hippocampus and appears to inhibit
LTP induction (Bellinger et al., 1993; Cunningham et al., 1996;
Katsuki et al., 1990; Murray and Lynch, 1998). Failing to confirm
such findings, Schneider et al. (1998) demonstrated that increased
local production of IL-1b in the hippocampus plays a role in LTP
maintenance. As noted by Schneider et al. (1998), this alternative
finding might have occurred because of the high concentration
levels used in previous studies, which were more comparable to
levels seen during pathological and inflammatory states then
normal physiological conditions. Subsequent work (i.e. Coogan
et al., 1999; Ross et al., 2003) has confirmed that at least under
physiological conditions IL-1b is required for LTP maintenance,
whereas, higher concentration of IL-1b, under pathophysiological
conditions, inhibits LTP. Together these findings suggest that IL-1
plays an intimate role in synaptic plasticity and that through these
mechanisms possibly an important role in memory consolidation
(see Fig. 1).
Cognitive-behavioural studies in animals (see Table 1 for
details) have repeatedly shown that IL-1b influences various
types of hippocampal-dependent memory (Brennan et al., 2003;
Yirmiya et al., 2002). Moreover, research by Depino et al. (2004),
has recently demonstrated that endogenous IL-1a also participates
in hippocampal memory processing. As reviewed by Pugh
et al. (2001), there is considerable evidence to suggest that IL-1
might under physiological conditions play a role in memory
consolidation processes. However, during stress, aging and
disease, IL-1 appears to elicit memory impairment (Pugh et al.,
2001). In support of these findings, IL-1b has recently been
demonstrated to play a dual role in hippocampal-dependent
memory processes (Avital et al., 2003; Goshen et al., 2007b). More
specifically, it was demonstrated by these authors that the
involvement of IL-1bin hippocampal-dependent memory follows
an inverted U-shape pattern, in that basal levels of IL-1b are
required for normal memory function, and any deviation from this
physiological range (either deletion or elevation) results in
impaired memory (Avital et al., 2003; Goshen et al., 2007b).
Research by Avital et al. (2003), further demonstrated that
impaired memory in IL-1 receptor type 1 knockout mice,
coincided with deficits in synaptic plasticity. Moreover, as
recently shown by Young et al. (2007, #234), increased levels
of IL-1 disrupts an LTP-associated spinal learning paradigm (Grau
et al., 2006), suggesting that IL-1 over-expression might impair
LTP-associated learning processes possibly throughout the
neuroaxis (Deak, 2007). Although not fully understood, these
findings provide strong evidence to support a direct link between
synaptic plasticity, IL-1 and cognitive functioning.
Finally, recent investigations which explored the involvement
of IL-1 in neurogenic processes during disease, stress and
inflammatory states (Ben Menachem-Zidon et al., 2007; Goshen
et al., 2007a; Kaneko et al., 2006; Koo and Duman, 2008; Spulber
et al., 2008), have demonstrated that IL-1 can mediate neurogenesis.
Although these processes have not been investigated during
physiological conditions, there is reason to suggest that this
relationship between IL-1 and neurogenesis might, in turn, have an
impact on hippocampal-dependent learning and cognitive processes
during health (Bruel-Jungerman et al., 2005; Drapeau et al.,
2003; Saxe et al., 2007; Shors et al., 2002). Future research should
therefore address the relationship between physiological levels of
IL-1 and neurogenesis, and how these processes might influence
cognitive function.
3.2. IL-6 impacts cognitive function via effects on neurogenesis and
synaptic plasticity
Despite evidence to suggest that IL-6 plays an important role in
neurodegenerative disease (Harding et al., 2005; Marsland et al.,
2006; Rosenberg, 2005; Schram et al., 2007; Weaver et al., 2002;
Wright et al., 2006), little is known about the biological actions of
IL-6 during health and how these processes influence cognition.
This section will therefore concentrate on what is known about the
physiological functions of IL-6 within the brain during health;
although data on how IL-6 over-expression might affect cognitive
function will be briefly discussed. As an introduction to these
biological functions of IL-6 in the brain, we briefly outline the
synthesis, receptor signalling and signal-transduction pathways of
this cytokine.
In the CNS IL-6 is principally synthesized by astrocytes, and to a
lesser extent, microglial, and neurons. As with other cytokines IL-6
Fig. 1. Schematic illustration of the involvement of IL-1 and IL-6 in Hebbian synaptic
plasticity, such as LTP and LTD. Essentially this process can be divided into three
stages. In stage 1, the simultaneous neuronal activity (firing) of both pre-synaptic
and post-synaptic neurons results in the induction of LTP. This induction of LTP
leads to the production of both IL-1 and IL-6 (stage 2). Finally in stage 3, LTP
maintenance is fine-tuned by the overall level of expression of both IL-1 (facilitates)
and IL-6 (blocks), thus influencing the consolidation of learning and memory.
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366358
exerts multiple physiological functions within the CNS, which are
both neuroprotective and neurodegenerative. IL-6 exerts these
biological effects through the formation of a hexameric receptor
ligand complex (i.e. the binding of IL-6 to IL-6 receptor, which then
leads to the homodimerization of gp130, the co-receptor of the IL-6
receptor), which subsequently induces signalling (Ward et al.,
1994). The IL-6 receptor, through alternative splicing and
shedding, also exists as a soluble form (sIL-6R), which unlike
most other soluble cytokine receptors, functions as an agonist. IL-6
mediated responses are, therefore, greatly enhanced by the
presence of sIL-6R (Van Wagoner et al., 1999; Van Wagoner and
Benveniste, 1999). Moreover, sIL-6R can activate signalling
responses in non-IL-6 cells (i.e. cells lacking IL-6 receptors) which
express gp130; i.e. through the binding of sIL-6R with gp130.
Distinct regions of gp130 activate specific signal-transduction
pathways, such as the JAK-STAT, Ras-MAPK and PI-3 kinase
(Hirano et al., 1997). Such findings might help explain the
redundancy and antagonistic effects seen by cytokine receptors,
especially the IL-6 family; although this remains to be clarified.
Recent studies suggest that neurogenesis is important for
cognitive function and modulating memory function, such as,
memory consolidation and some types of hippocampal-dependent
learning (Bruel-Jungerman et al., 2005; Drapeau et al., 2003; Saxe
et al., 2007; Shors et al., 2002). Research by Dupret et al. (2007) has,
for instance, shown that learning-induced regulation of adult
neurogenesis plays an important role in spatial learning, and that
dysregulation of hippocampal neurogenesis may underlie age
related memory deficits (Drapeau et al., 2003, 2007). Interestingly,
IL-6 has been shown to be an important regulator of neurogenesis.
As shown by Vallieres et al. (2002), adult transgenic mice which
over-express IL-6 by astroglia demonstrated a 63% reduction in
neurogenesis in the hippocampal dentate gyrus. Furthermore,
research by Monje et al. (2003) has also linked increased IL-6 levels
with neural stem cell dysfunction and an associated decline in
learning and memory. Such findings demonstrate that the longterm
exposure to IL-6, as seen in normal aging (Godbout and
Johnson, 2004) and certain neurodegenerative diseases can
interfere with cognitive functioning by impairing adult neurogenesis.
However, what remains to be clarified is whether basal levels
of IL-6 during health participate in cognitive processes.
As investigated by Braida et al. (2004), transgenic mice not
expressing IL-6 demonstrated improved cognitive functioning, as
indicated by improved radial maze learning and a reduced amnesic
effect of scopolamine during passive avoidance testing compared
to wild-type mice (see Table 1). In particular, both young and old
IL-6 transgenic mice, in comparison to wild-type mice, demonstrated
superior and faster acquisition, in terms of both reduced
number of working memory errors and shorter time and higher
percentage to reach the criterion. On the other hand, research by
Hryniewicz et al. (2007), has shown that IL-6 deficiency disrupts
object recognition memory, as indicated by less time spent
exploring the novel object, which suggests that transgenic IL-6
mice fail to distinguish novel objects from familiar objects (see
Table 1). One possible explanation for this discrepancy is that basal
levels of IL-6 influence neurogenesis, which in turn mediates some
types of hippocampal-dependent forms of learning and memory
but not others; although other mechanisms involving choline
acetyltransferase (Itzhak and Achat-Mendes, 2004), m-opioid
Table 1
Cognitive-behavioural studies investigating the involvement of cytokines in learning and memory processes.
Study Species Animal model Cytokine Cognitive-behavioural test Findings
Yirmiya et al. (2002) Rat Long Evans hooded rats (i.c.v. IL-1b,
IL-1ra or saline injections)
IL-1 Passive avoidance and
Morris water maze
IL-1 plays a critical role in hippocampaldependent
learning and memory processes
Brennan et al. (2003) Rat Sprague-Dawley rats (i.p. IL-1b
injections ­ 1, 3, 6 mg/kg or saline)
IL-1 Leverpress avoidance task Low or moderate doses of IL-1 improved
performance on leverpress avoidance task
Depino et al. (2004) Rat Wistar rats IL-1 Inhibitory avoidance task Endogenous hippocampal IL-1 modulates a
fear-motivated learning task; suggesting IL-1
to be apart of hippocampal memory processing
Pugh et al. (2001) Rat Rats ­ induced IL-1 activity
(i.c.v. IL-1b, gp120 and i.p. LPS
injections and social isolation)
IL-1 Auditory and contextual
fear conditioning
Increased IL-1 levels adversely affect
hippocampal-dependent memory
consolidation processes
Avital et al., 2003 Mouse wt and IL-1rKO mice 129/
Sv  C57BL/6 background
IL-1 Morris water maze and
contextual fear
conditioning
IL-1 participates in hippocampal-dependent
memory processes synaptic plasticity
Goshen et al. (2007a,b) Mouse wt and IL-1raTG mice (C57BL/
6 Â CBA) and wt and IL-1rKO mice
(129/Sv  C57BL/6)
IL-1 Morris water maze and
contextual fear
conditioning
IL-1 exerts a dual role in hippocampaldependent
memory processes; an inverted
U-shaped pattern ­ i.e. the absence and
over-expression of IL-1 impairs memory
Braida et al. (2004) Mouse wt and IL-6/ mice CBA
 C57BL/6 background
IL-6 Passive avoidance and
radial maze
Transgenic IL-1 knockout mice demonstrated
improved radial maze and passive avoidance
learning
Hryniewicz et al. (2007) Mouse wt and IL-6/ mice C57BL/6
background
IL-6 Novel object recognition
task
IL-6 knockout mice displayed impaired
recognition memory, suggesting that
endogenous IL-6 plays a role in recognition
memory
Baune et al. (2008) Mouse wt, TNF/, TNF R1 and R2
knockout C57BL/6 background
TNF Barnes maze and novel
object recognition task
Absence of TNF has detrimental effects on
cognition performance, that is not receptor
specific
Fiore et al. (1996) Mouse wt and Tg6074 (TNF overexpression)
CBA Â C57Bl/6
background
TNF Passive avoidance Transgenic mice demonstrated altered learning
and memory process; a retardation in passive
avoidance acquisition
Fiore et al. (2000) Mouse wt, Tg6074 and TgK3 (TNF
over-expression) CBA Â C57BL/6
background
TNF Passive avoidance and
Morris water maze
TNF over-expression in the brain results in
disrupted learning capabilities and altered NGF
and NPY expression levels
Aloe et al. (1999) Mouse wt, Tg6074 and TgK3 (TNF
over-expression) CBA Â C57BL/6
background
TNF Morris water maze Transgenic mice demonstrated memory
impairments and altered NGF and BDNF
expression levels
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366 359
receptors, neurodevelopmental anomalies and synaptic plasticity
cannot be ruled out (see Braida et al., 2004; Gurwitz, 1997). Despite
apparently opposite results, these two experiments do however
demonstrate that endogenous IL-6 plays an important role in
cognitive function during physiological conditions.
As repeatedly shown, IL-6 also appears to influence synaptic
plasticity (Balschun et al., 2004; Jankowsky et al., 2000; Li et al.,
1997; Tancredi et al., 2000). As indicated by Li et al. (1997),
exogenous IL-6 can suppress the induction of LTP without
disrupting previously established LTP. This inhibitory effect of
IL-6 on synaptic plasticity has been subsequently shown by
Tancredi et al. (2000), to be mediated through mitogen-activated
protein kinase ERK (MAPK/ERK). The demonstration that IL-6 is upregulated
following LTP induction (Jankowsky et al., 2000) has
provided further evidence that IL-6 may be involved in synaptic
plasticity. In support of such findings, Balschun et al. (2004), have
shown that neutralizing IL-6 after tetanisation strengthens LTP
maintenance. According to the authors, IL-6 appears to play a role
in synaptic plasticity opposite to IL-1 and LTP maintenance
(Balschun et al., 2004) (see Fig. 1). It has, therefore, been
hypothesized that IL-6 under basal conditions may regulate or
fine-tune the consolidation of long-term synaptic plasticity and
hippocampal-dependent learning by opposing, in a negativefeedback
fashion, the effects of IL-1 on LTP maintenance (Balschun
et al., 2004) and/or by curtailing synaptic enhancement at
neighbouring synapses (Jankowsky et al., 2000). Further research
is needed to elucidate the role in which IL-6 plays in synaptic
plasticity, neurogenesis and cognitive function, during health and
pathological conditions in which increased levels of IL-6 have been
implicated.
3.3. TNF alpha influences cognitive function through direct effects on
LTP and synaptic scaling
Tumor necrosis factor is a pro-inflammatory cytokine which
has been shown to exert physiological, neuroprotective (Cheng
et al., 1994; Gemma et al., 2007; Pan and Kastin, 2001; Schwartz
et al., 1994) and neurodegenerative (Perry et al., 2001) effects
within the nervous system. These pleiotropic effects are exerted by
TNF via activation of two receptors, TNF-p55 receptor and TNF-p75
receptor. Often referred to as TNF-R1 and TNF-R2 respectively,
these two distinct receptors have been shown to elicit different
molecular and cellular responses (Baud and Karin, 2001; Chen and
Goeddel, 2002; MacEwan, 2002a,b; Wajant et al., 2003). For
instance, TNF-R1 has been shown to initiate the activation of
caspases and ultimately apoptosis (MacEwan, 2002a,b). This
`death-signalling' intracellular pathway appears to be activated
by a specific cytoplasmic domain identified in TNF-R1, referred to
as the `death domain'. TNF-R2 lacks this `death domain' and
appears to inhibit the activation of caspases and protect against
apoptosis; albeit there is some evidence to suggest that TNF-R2
activation can induce cell death (see Wajant et al., 2003 for further
details).
Recent research shows considerable advancement in the
understanding of TNF bioactivity within the CNS. For example,
TNF has the biological property to act as a neuromodulator within
the brain (Blatteis, 1990; Szelenyi, 2001; Vitkovic et al., 2000a,b).
Moreover, TNF has been shown to play a role in both glutamate
excitotoxicity (i.e. by inhibiting glutamate transporters on astrocytes)
and glutamate transmission (see Pickering et al., 2005 for a
review). More specifically, Beattie et al. (2002) demonstrated that
glial-derived TNF markedly influenced synaptic efficacy by upregulating
surface expression of a-amino-3-hydroxy-5-methyl-4isoxazolepropionic
(AMPA) receptors. In support of these findings,
it was established subsequently by Stellwagen et al. (2005) that the
up-regulation of AMPA receptors by TNF is mediated through TNFR1
and phosphatidylinositol 3 (PI3) kinase-dependent processes.
Interestingly, it was also determined by these researchers, that TNF
simultaneously causes a decrease in synaptic inhibition via
endocytosis of GABAA receptors (Stellwagen et al., 2005). Such
findings support a neuromodulatory role for TNF within the brain
and suggest a possible role for TNF in synaptic plasticity.
The stability and cycling of AMPA receptors at synapses has
been shown to be an essential process in both LTP and LTD
(Malenka and Bear, 2004; Malenka and Nicoll, 1999). Since TNF-a
has been shown to up-regulate AMPA receptors (Beattie et al.,
2002; Stellwagen et al., 2005) it has been postulated that TNF
might serve an essential function in Hebbian synaptic plasticity
and possibly learning and memory. Research by Tancredi et al.
(1992) and Cunningham et al. (1996), but not others (i.e.
Stellwagen and Malenka, 2006) have demonstrated that pathophysiological
levels of TNF inhibit LTP in the dentate gyrus of rat
hippocampal slices. In support of these findings, Butler et al. (2004)
determined that the inhibitory effect of TNF on LTP is a biphasic
response. More specifically, their research demonstrated that the
inhibition of early phase LTP by TNF is dependent on a p38
mitogen-activated protein kinase process, whereas, late phase LTP
inhibition is p38 MAPK-independent (Butler et al., 2004).
Subsequent research (i.e. Cumiskey et al., 2007) has further shown
that TNF inhibition of LTP is dependent on TNF-R1 and mGlu5receptor
activation. In addition to these findings, Albensi and
Mattson (2000) have demonstrated a role for endogenous TNF and
NF-kB signalling in LTD induction. Unlike the exogenous studies
previously mentioned, the results from Albensi and Mattson
(2000) provide evidence for a TNF-mediated physiological role in
synaptic plasticity.
Although these results support a role for TNF in LTP and LTD,
alternative suggestions have been made (Stellwagen and Malenka,
2006). In a series of elegant experiments, Stellwagen and Malenka
(2006) demonstrated that endogenous glial-derived TNF is critical
for homeostatic synaptic scaling. In particular, it was shown that
during prolonged inactivity TNF shifts neurons towards more
excitation and less inhibition (Stellwagen and Malenka, 2006) (see
Fig. 2). Such findings support recent studies that glial cells play an
essential role in neuronal processing, synaptic integration and
synaptogenesis (Bains and Oliet, 2007; Bezzi and Volterra, 2001;
Halassa et al., 2007a; Slezak and Pfrieger, 2003; Turrigiano, 2006;
Vesce et al., 2001). Although poorly understood, glial modulation
of neuronal activity appears to involve cytokines such as TNF and
BDNF (see Halassa et al., 2007b; Rutherford et al., 1998; Swanwick
et al., 2006; Volterra et al., 2002 for details). Moreover, there is now
reason to believe that glial­neuronal homeostatic synaptic
plasticity mediated by TNF plays an essential role in learning
and memory (Bains and Oliet, 2007; Turrigiano, 2006, 2007). The
clarification of TNF's participation in synaptic plasticity is not only
warranted, but might otherwise explain cognitive-behavioural
findings (see Table 1 for details) that disruption of these
physiological processes leads to cognitive impairment.
As recently shown by this research group the presence of TNF, in
mice, under immunologically non-challenged conditions is essential
for normal functions of memory and learning (Baune et al.,
2008). Cognitive impairment has also been demonstrated in
transgenic mice over-expressing TNF (Aloe et al., 1999; Campbell
et al., 1997; Fiore et al., 1996, 2000). This TNF over-expressionassociated
decline in cognitive function might relate to changes in
synaptic plasticity (Small, 2008; Tobinick and Gross, 2008a) and/or
possibly decreased NGF levels (Fiore et al., 2000); which has been
shown to impair long-term potentiation (Kelly et al., 1998, 2000)
and cause neurodegeneration (Capsoni and Cattaneo, 2006;
Capsoni et al., 2000, 2002). Future research is, therefore, needed
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366360
to unravel the participation of TNF in synaptic plasticity and
cognitive function during health and disease.
3.4. Other potential mechanisms by which cytokines might mediate
cognitive processes
Based on the pleiotrophic biological properties of cytokines, it is
plausible that cytokines might influence synaptic plasticity and/or
cognitive processes via alternative mechanisms then those stated
above (see Fig. 3 for schematic illustration). For instance, proinflammatory
cytokines, such as IL-1 and TNF have been shown to
activate small G-proteins such as, Ras, Rho, Rac and Rap1
(MacEwan, 2002a,b; Williams et al., 2008). Of particular interest
in regards to cytokine-mediated cognition is recent evidence that
glia-derived TNF inhibits neurite outgrowth and branching by
activating RhoA in neurons (Neumann et al., 2002). Since
synaptogenesis and dendritic branching serve an essential role
in synaptic plasticity and learning and memory processes (Muller
et al., 2000, 2002; Remy and Spruston, 2007), TNF might exert
profound effects on cognitive functioning through such mechanisms.
Although this has not be well studied, recent evidence has
implicated Rho in mental retardation, synaptic plasticity (i.e.
synaptogenesis and dendritic branching) and cognition (Chechlacz
and Gleeson, 2003; Govek et al., 2005; Meng et al., 2005; Newey
et al., 2005; Ramakers, 2002). Future research is, therefore, needed
to clarify the role in which cytokines, such as TNF, might play in
synaptogenesis, dendritic branching and how these processes
might relate to Rho activation and cognitive processes.
Other evidence has suggested that P2x7 receptors (P2 purinergic
receptors) serve an important role in neuronal­glia communication
and cytokine-mediated processes within the brain (Bennett, 2007;
Lister et al., 2007; Sperlagh et al., 2006). Purinergic receptors are
divided into two major families, which bind adenosine (P1
receptors), and ATP, ADP, UTP or UDP (P2 receptors). P2 purinergic
receptorsarefurther dividedinto ligand-gated channelor ionotropic
receptors (P2X receptors) and G-protein coupled receptors (P2Y
receptors). In particular, P2x7 has been recognized as an important
receptor for several inflammatory molecules, such as IL-1, IL-6 and
TNF. In particular, it is believed that P2x7 receptors play a key role in
the brain cytokine response to immune stimuli that leads to sickness
behaviour and possibly depression and/or cognitive dysfunction
(Bennett, 2007; Mingam et al., 2008). Future research should also be
directed at elucidating such possible mechanisms and pathways in
both disease and health.
3.5. Other cytokines potentially influencing cognitive function
3.5.1. Alpha1-antichymotrypsin (ACT)
Biochemical and genetic studies indicate that ACT is important
in the pathogenesis of Alzheimer's disease. In a study using several
lines of transgenic/knockout mice it was shown that human ACT
separately and synergistically with ApoE facilitate both diffuse A
beta immunoreactive and fibrillar amyloid deposition, thus
promoting cognitive impairment in aged PDAPP(V717F) mice.
The degree of cognitive impairment was correlated with the ApoEand
ACT-dependent hippocampal amyloid burden (Nilsson et al.,
2004). Further supportive data for the involvement of ACT in
cognitive decline stems from a population-based study showing
that the serum inflammatory protein alpha1-antichymotrypsin
was associated with cognitive decline in older persons (Dik et al.,
2005).
In a clinical genetic study among patients with a clinical
diagnosis of probable AD and patients with early onset AD, the ACT
gene appeared to influence the early clinical development of the
disease and the interaction of the ACT and ApoE genes affected
clinical progression of AD (Licastro et al., 2005). Interestingly, in a
study among 108 patients with late onset AD, the authors report
an association between the ACT polymorphisms but they failed
to show an association between ACT serum levels and ACT
polymorphism as well as a correlation between ACT serum levels
and cognitive function (McIlroy et al., 2000).
In summary, the data suggest consistent genetic findings of ACT
polymorphism effects on cognitive function in AD in human which
is in line with results from some animal studies; however no
information is available to date on the direct involvement of ACT in
molecular mechanisms of learning and memory.
3.6. Interferon-gamma (IFN-gamma)
In a recent animal study it was demonstrated that the cytokine
IFN-gamma enhances neurogenesis in the dentate gyrus of adult
mice and improves the spatial learning and memory performance
of the animals (Baron et al., 2008). In older mice, the effect of IFNgamma
is more pronounced in both wild-type mice and mice with
Alzheimer's-like disease and is associated with neuroprotection
(Baron et al., 2008). The authors suggest that limited amounts of
IFN-gamma in the brain shape the neuropoietic milieu to enhance
neurogenesis, possibly representing the normal function of the
immune system in controlling brain inflammation and repair
(Baron et al., 2008).
It is well known that cell renewal in the adult central nervous
system is limited, and is blocked under inflammatory brain
conditions. In an animal study it was demonstrated that neurogenesis
of adult neural progenitor cells in mice are blocked by
inflammation-associated microglia. Microglia activation occurred
Fig. 2. Schematic illustration of the involvement of TNF in synaptic scaling a nonHebbian
form of synaptic plasticity. In brief, a prolonged period of neuronal
inactivity leads to a decrease in synaptic strength, which triggers, via glial­neuronal
communication, the release of TNF by astrocytes. In a reciprocal fashion, the
released TNF by astrocytes influences the activity of the post-synaptic neuron
resulting in an increase in synaptic strength. Collectively, this helps to maintain
neuronal activity `synaptic scaling' and learning and memory functions.
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366 361
through low level of IFN-gamma (Butovsky et al., 2006). Thus, it is
suggested that IFN-gamma has the potential to stimulate neurogenesis,
and the possibility to play a role in development and repair of
the CNS (Kim et al., 2007). Moreover, since IFN-gamma is able to
stimulate neurogenesis, a potential neural correlate of memory
consolidation, it can be hypothesized that IFN-gamma has the
potential ability to directly or indirectly subserve memory consolidation;
however testing of this hypothesis is still outstanding.
Finally, clinical reports suggest that interferon (IFN) therapy
is associated with neuropsychiatric side-effects including cognitive
dysfunction and mood syndromes with varying rates of IFNinduced
depression approaching up to 50% in recent studies
(Valentine and Meyers, 2005).
3.7. Interleukin-2 (IL-2)
Relatively little direct evidence for the involvement of IL-2 in
cognitive function is available to date. In a clinical study conducted
among cancer patients, subcutaneous IL-2 was shown to impair
spatial working memory and lower accuracy of planning abilities.
In contrast, patients treated with IFN-alpha did not show any
impairment in performance accuracy in these tasks but showed
longer latencies in reaction time. Most of these early alterations
persisted at the end of the first month of treatment without any
obvious sign of worsening (Capuron et al., 2001).
The neurotoxic effects of IL-2 in the above human study are
supported by findings from animal research which showed that IL-
2 gene deletion alters the neuroimmunological status of the mouse
hippocampus through a dysregulation of cytokines produced by
CNS cells associated with increased hippocampal neurogenesis in
male mice (Beck et al., 2005b).
3.8. Cytokine signalling pathways in the injured brain
Only limited evidence on the manipulations of the cytokines
induced effects on cognition through pharmacological interventions
has emerged over the past 10 years. In an experimental
study, the effect of systemic administration of human recombinant
Fig. 3. Schematic representation of the key cytokine-mediated molecular mechanisms and neuronal­glial interactions that subserve synaptic plasticity and learning and
memory processes in the brain. During pathological conditions microglial interact with neurons, possibly via P2x7 receptors, to induce a neuroinflammatory response
characterized by an up-regulation of cytokines, such as, IL-1, IL-6 and TNF, which can then alter the normal balance and physiological function of cytokines in synaptic
plasticity. Alternatively, during normal physiological conditions astrocytes play a central role in synaptic integration and neuronal processing. In particular, the release of TNF
from astrocytes (often due to prolonged synaptic inactivity) results in the activation of several different downstream processes, such as (1) activation of small G proteins
(rhoA) which can have profound effects on dendritic branching and synaptogenesis, (2) up-regulation of AMPA receptors via activation of TNF receptor 1 (TNF-R1) and PI3
kinases, with the resultant rise in AMPA receptors leading to an increase in synaptic activity, (3) activation of TNF-R1 and metabotropic glutamate receptor 5 (mGlu5) leading
to either early phase long-term potentiation (LTP) inhibition (via p38 MAPK dependent activity) or late phase LTP inhibition (via p38 MAPK independent activity) and (4) the
activation of transcription factor NF-kB resulting in the induction of long-term depression (LTD). Alternatively, normal synaptic activity can lead to the activation of NMDA
receptors during post-synaptic depolarization which then leads to an influx of intracellular calcium (Ca+) and further signal transduction. Collectively these processes lead to
the induction of LTP and the up-regulation of IL-1 and IL-6. IL-1 and IL-6 exert, via similar downstream mechanisms, opposing effects on the maintenance of LTP, which works
in a negative-feedback fashion to fine-tune the consolidation of long-term synaptic plasticity. Collectively all these processes can influence LTP, LTD, synaptic scaling and
possibly other cellular mechanisms that subserve learning and memory.
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366362
interleukin-1 receptor antagonist (rhIL-1ra) on behavioral outcome
was evaluated after brain injury in Sprague-Dawley rats
(Sanderson et al., 1999). Postinjury administered high-dose rhIL-
1ra significantly attenuated posttraumatic neuronal loss in the
injured hippocampal CA3 region, dentate hilus, and cortex but
impaired recovery of motor function at 7 days after trauma. In
addition, postinjury administration of rhIL-1ra significantly
attenuated cognitive deficits. These results suggest that inhibitors
of cytokine pathways may be therapeutically useful for the
treatment of brain trauma. Applying a similar animal study design
this time using monoclonal antibodies (mAB), it was found that the
treatment with either TNF- or IL-6-mAB had no effect on neurological
motor, cognitive function or brain edema during the first
post-injury week (Marklund et al., 2005). Studies using other than
vascular models of cognition show that anti-TNF treatment of
humans with Alzheimer's disease may lead to rapid cognitive
improvement. However, it is unclear from this human study which
TNF receptor mediated the improvement (Tobinick, 2007; Tobinick
et al., 2006; Tobinick and Gross, 2008b).
Antagonistic effects of celecoxib, a selective cycloxygenase-2
(COX-2) inhibitor, on age-dependent increased cytokine expressions
of IL-1beta and TNF in the hippocampus in the aging rat were
investigated (Casolini et al., 2002). Since the chronic oral treatment
with celecoxib was able to contrast the age-dependent increase in
hippocampal levels of pro-inflammatory markers and circulating
anti-inflammatory corticosterone (provided that intervention
started at an early stage of aging), the results suggest a preventive
potential of COX-2 inhibitors. However, it is still speculative that
age-related impairments in cognitive ability may be ameliorated as
cognition-like behaviour was not assessed in this animal study
(Casolini et al., 2002).
Cytokine effects can also interact with receptors of other brain
systems mediating disease states such as pain. In an animal study
investigating the role of peripheral groups I and II metabotropic
glutamate receptors (mGluRs) in interleukin-1beta (IL-1beta)induced
mechanical allodynia in the orofacial area, it was found
that the peripheral group I mGluR antagonists blocked the IL-
1beta-induced mechanical allodynia, while peripheral group II
mGluR agonists produced anti-allodynic effects on IL-1betainduced
mechanical allodynia in the orofacial area of rats (Ahn
et al., 2005).
The limited studies to date on cytokine receptor involvement in
cognitive function in humans and animal models indicate the need
for further research covering a larger range of cytokines as well as
inflammatory diseases to enhance the understanding of the
underlying mechanisms, but also with the aim to translate the
research into clinical pharmacological applications for the treatment
of neuropsychiatric diseases characterized by cognitive
impairment such as dementia and depression.
4. Limitations and future research
The research on cytokine involvement with cognitive function
and cognitive impairment leading to the proposed cytokine model
of cognitive function is largely based on animal studies as well as
clinical studies in humans as evaluated in this review. While
animal studies help to understand the molecular and cellular
mechanisms of learning and memory and cognitive function,
clinical studies contribute to the understanding of cognitive
impairment in humans with circumscribed diseases such as
dementia. The major limitations of the research on this topic are
the relatively few cytokines for which sufficient evidence of their
molecular and cellular effects related to cognitive function and/or
learning and memory is readily available and secondly the largely
missing link of translational research from basic science to clinical
applications. This is evidenced by the few published studies in
humans applying the principle of cytokine blockade in order to
improve cognitive performance as demonstrated with anti-TNF
treatment in dementia (Tobinick et al., 2006).
The research on cytokines in cognitive function in humans is also
limited by the difficulty to make use of pharmacological receptor
blockade of cytokine effects involved in cognitive function. The
development of receptor specific antibodies for the use in humans
without causing significant side-effects and the translation
from animal research would hold potential for the development
of new treatments for various neuropsychiatric conditions related
with cognitive decline. Finally, the translation of animal research
assessing cognition-like behaviour to more complex human
behaviour is a challenge in itself. Although the animal models
provide reliable and valid cognitive measures, neurospychological
concepts in humans such as word fluency, executive function and
consciousness are difficult to capture or represent in animal models.
However, future research on cytokines in cognitive function would
benefit from an approach in which line of evidence for cytokine
effects on cognitive function is created including animal models and
clinical applications covering molecular cellular and clinical studies.
5. Clinical implications and conclusions
There is now considerable evidence to suggest that cytokines
mediate essential nervous system functions during health that lie
outside their functions in traditional immune and inflammatory
processes (Bauer et al., 2007; Pickering and O'Connor, 2007;
Vitkovic et al., 2000a; Viviani et al., 2007). In particular, data
suggests that pro-inflammatory cytokines, such as IL-1, IL-6 and
TNF, serve a specific function in synaptic plasticity and cognitive
processes. Additional evidence is seen for effects of ACT and IFGgamma
on cognitive function. Further clarification and future
inclusion of other potential candidates of the suggested cytokinemediated
model of cognition will not only provide better understanding
of these physiological processes, but might also have
direct relevance to the understanding of pathological changes seen
in certain neuropsychiatric diseases. For instance, as suggested by
Small (2004, 2008), the progression of Alzheimer's disease might
be driven by exaggerated, TNF-mediated, synaptic scaling during
prolonged inactivity caused by b-amyloid. It must be emphasized
here, that it is the physiological function of TNF in synaptic scaling
(i.e. thought to subserve cognitive processes) and not inflammatory
or pathophysiological processes of TNF that is postulated to be
driving disease progression. Although it remains to be clarified,
clinical data obtained by Tobinick (2007), Tobinick et al. (2006) and
Tobinick and Gross (2008a) suggests that the rapid cognitive
improvement seen in Alzheimer's disease patients receiving antiTNF
treatment (i.e. perispinal administration of etanercept) maybe
the result of reversed excess TNF-mediated synaptic plasticity
dysregulation. Future research aimed at elucidating the role in
which TNF plays in normal synaptic plasticity might lead to better
disease understanding and therapeutic intervention.
Depression might also represent an exaggerated form of
cytokine-mediated behaviour, in that cytokines naturally exert a
normal role in the brain that manifests as `sickness behaviour' in
disease models with over-expressed cytokines (Dantzer et al., 2008).
This natural behavioural change is both adaptive and physiological,
but during prolonged inflammation and/or psychological stress
might lead to the pathogenesis of depression. The `hijacking' of these
physiological processes during disease might also explain the
high comorbidity between neurodegenerative diseases and depression
(Caballero et al., 2006) and why depression is a risk factor
for neurodegenerative diseases (McDonald et al., 2003; Ownby et al.,
2006). The clinical application of anti-inflammatory treatments
J. McAfoose, B.T. Baune / Neuroscience and Biobehavioral Reviews 33 (2009) 355­366 363
in depression is still outstanding, although the present basic science
data are suggestive of such a translation research approach.
Finally, the clarification and understanding of the physiological
functions of cytokines within the brain might also provide insight
into age-associated cognitive decline (Bodles and Barger, 2004;
Griffin et al., 2006; Lynch, 1998; Maher et al., 2005; Nolan et al.,
2005).
In summary, the review provides evidence that cytokines
mediate essential nervous system functions during health that lie
outside their functions in traditional immune and inflammatory
processes. In particular, the cytokines IL-1eta, IL-6 and TNF-alpha
hold biological features at the molecular level, such as synaptic
plasticity, neurogenesis and neuromodulation, and at cellular
mechanisms subserving learning, memory and cognition under
physiological conditions. These cytokine-mediated cognitive processes
have significant implications in healthy states as well as in the
long-term development and pathogenesis of specific neuropsychiatric
disorders such as major depression and dementia.
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