Research reportBehavioral profile of P2X7 receptor knockout mice in animal models of depression and anxiety: Relevance for neuropsychiatric disorders
Introduction
Depression is recognized as having high prevalence in several medical conditions including infectious, autoimmune and neurodegenerative diseases. Over the last two decades an increasing body of evidence has indicated a strong relationship between depression and immunological dysfunction in depressed patients [5], [17], [42]. It has been suggested that excessive secretion of macrophage cytokines, interleukin-1β (IL-1β), interferon-α (INF-α) and tumor necrosis factor-α (TNF-α) could be a potential causative factor for the disorder [58]. Several lines of evidence support a role for cytokines in depression: depression is accompanied by signs of immune activation and elevated levels of pro-inflammatory cytokines [32], [49], [64], pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 may produce “sickness behavior” and mediate many of the physiological and behavioral changes associated with depression [7], [16], [33], [51], cytokines can induce neuroendocrine and neurochemical changes similar to a depressive syndrome [20], [26], [33], [51], and clinical use of cytokines like IFN-α produces depressive-like symptoms that can be attenuated with antidepressant treatments [30].
The purinergic P2X receptors are ligand-gated ion channels activated by adenosine 5′-triphosphate (ATP) and other related nucleotides, and are formed by seven subunits that are encoded by different genes (P2X1–P2X7) [47]. Purinergic receptors are present in mammalian cells such as brain, autonomic and spinal cord neurons, glial cells and immune cells [47]. P2X7 receptors can modulate cell growth, proliferation, cause apoptosis and cell death [1], [23]. In addition, the P2X7 receptor can modulate the maturation and release of IL-1β in macrophages and microglia and is involved in general mechanisms implicated in inflammation and progression of neurodegenerative diseases [22], [24], [25], [29], [39].
The P2X7 receptor subunit gene in humans is located close to the tip of the long arm of chromosome 12. Previous genetic studies identified a susceptibility locus in the region of chromosome 12q23–24 that suggested a linkage with mood disorders such as bipolar disorder and major depressive disorder [2], [14], [38]. Recently, an increased vulnerability to bipolar affective disorders associated with single nucleotide polymorphisms in the chromosome 12q24.31 region that encodes for the P2X7 receptor gene has been reported [8], [56], [57].
In view of the involvement of P2X7 receptors in cytokine release, inflammation, and apoptotic cell death, it is reasonable to hypothesize that P2X7 receptors could play a role in the pathology of depression. Considering that cytokines like IL-1β can induce behavioral and physiological changes that resemble depression, that immune activation and altered levels of pro-inflammatory cytokines are associated with major depression, and that P2X7 receptors play an important role regulating the release of pro-inflammatory cytokines, it could be proposed that the inactivation of P2X7 receptors might result in antidepressant-like effects and might represent a potential target for the treatment of depression.
To investigate the role of P2X7 receptors in depression- and anxiety-like behaviors, mutant P2X7 receptor knockout (KO) mice and wild type (WT) mice were tested in several well characterized preclinical paradigms used to evaluate depression- and anxiety-like behaviors.
Section snippets
Generation of mutant P2X7 receptor knockout mice
The generation of P2X7 receptor gene KO mice has been previously described [31], [59]. These mice show altered ATP-stimulated cytokine processing [59] and reduced signs of experimental arthritis [31]. P2X7 receptor mutant mice used in the present studies were purchased from Lexicon Genetics Incorporated (The Woodlands, TX) and were generated based on previously established methodology [59]. The null targeting vector was derived using the Lambda knockout shuttle (KOS) system [65]. The Lambda KOS
Mouse peritoneal macrophages IL-1 release assay
To confirm that macrophages from P2X7 receptor KO mice lack the capacity to release IL-1β mediated by stimulation of P2X7 receptor [59], resident peritoneal macrophages from either WT or P2X7 receptor KO mice (n = 5/group) were primed with LPS and then stimulated with varying concentrations of BzATP (Fig. 1). In the WT mice, there was a dose related increase in the level of IL-1β released into the supernatant. When the macrophages from the P2X7 KO mice were stimulated with BzATP no measurable
Discussion
The inability of BzATP to stimulate the release of IL-1β peritoneal macrophages from P2X7 receptor KO mice relative to WT controls [59] was confirmed in the present study. Interestingly, the present data demonstrate that P2X7 receptor KO mice displayed antidepressant-like behaviors in two behavioral models: the tail suspension test and the forced swim test. In these models that are widely used for screening of antidepressant compounds [52], [61], P2X7 receptor KO mice exhibited significantly
Acknowledgement
This research has been funded by Abbott Laboratories.
References (68)
- et al.
Predisposition locus for major depression at chromosome 12q22–12q232
Am J Hum Genet
(2003) - et al.
Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons
Trends Neurosci
(2006) - et al.
Cytokines, stress, and depressive illness
Brain Behav Immun
(2002) - et al.
A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice
Int Immunopharmacol
(2006) - et al.
Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain
Pain
(2005) Exploratory behavior models of anxiety in mice
Neurosci Biobehav Rev
(1985)- et al.
The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice
Neurosci Biobehav Rev
(2005) - et al.
Effects of chronic mild stress on performance in behavioural tests relevant to anxiety and depression
Physiol Behav
(1994) - et al.
Differential effect of a single high dose of the tricyclic antidepressant imipramine on interleukin-1beta and tumor necrosis factor-alpha secretion following an in vivo lipopolysaccharide challenge in rats
Int J Immunopharmacol
(1999) - et al.
Purinergic receptors are part of a signaling system for keratinocyte proliferation, differentiation, and apoptosis in human fetal epidermis
J Invest Dermatol
(2003)
The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity
Neuroscience
Cytokine production and treatment response in major depressive disorder
Neuropsychopharmacology
Behavioral effects of cytokines
Brain Behav Immun
The in vitro immunosuppressive effects of moclobemide in healthy volunteers
J Affect Disord
Rapid secretion of interleukin-1beta by microvesicle shedding
Immunity
Evidence for an immune response in major depression: a review and hypothesis
Prog Neuropsychopharmacol Biol Psychiatry
Effects of unpredictable chronic mild stress on anxiety and depression-like behavior in mice
Behav Brain Res
Altered response to benzodiazepine anxiolytics in mice lacking GABA B(1) receptors
Eur J Pharmacol
Trophic actions of extracellular nucleotides and nucleosides on glial and neuronal cells
Trends Neurosci
Inflammatory markers and depressed mood in older persons: results from the Health Aging and Body Composition study
Biol Psychiatry
Chronic mild stress alleviates anxious behaviour in female mice in two situations
Behav Processes
The macrophage theory of depression
Med Hypotheses
Altered cytokine production in mice lacking P2X(7) receptors
J Biol Chem
Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65
Brain Res
Tricyclic antidepressants inhibit IL-6 IL-1 beta and TNF-alpha release in human blood monocytes and IL-2 and interferon-gamma in T cells
Immunopharmacology
Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents
Neuropsychopharmacology
Purinergic signalling: pathophysiological roles
Jpn J Pharmacol
Anhedonic and anxiogenic effects of cytokine exposure
Adv Exp Med Biol
Cytokines, stress and depressive illness: brain-immune interactions
Ann Med
Cytokines as a precipitant of depressive illness: animal and human studies
Curr Pharm Des
Analysis of single nucleotide polymorphisms in genes in the chromosome 12Q24 31 region points to P2RX7 as a susceptibility gene to bipolar affective disorder
Am J Med Genet B Neuropsychiatr Genet
The effects of chronic antidepressant treatment in an animal model of anxiety
Psychopharmacology (Berl)
Genome scan of pedigrees multiply affected with bipolar disorder provides further support for the presence of a susceptibility locus on chromosome 12q23–q24, and suggests the presence of additional loci on 1p and 1q
Psychiatr Genet
Cytokine-induced sickness behavior: mechanisms and implications
Ann N Y Acad Sci
Cited by (183)
Purinergic P2X7 receptor-mediated inflammation precedes PTSD-related behaviors in rats
2023, Brain, Behavior, and ImmunityAstrocytes and major depression: The purinergic avenue
2022, NeuropharmacologyStress induced microglial activation contributes to depression
2022, Pharmacological Research