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Long-term effects of maternal immune activation on depression-like behavior in the mouse.

ABSTRACT: Depression is a debilitating mental disease affecting a large population worldwide, the pathophysiological mechanisms of which remain incompletely understood. Prenatal infection and associated activation of the maternal immune system (MIA) are prominently related to an increased risk for the development of several psychiatric disorders including schizophrenia and autism in the offsprings. However, the role of MIA in the etiology of depression and its neurobiological basis are insufficiently investigated. Here we induced MIA in mice by challenge with polyinosinic:polycytidylic phosphate salt-a synthetic analog of double-stranded RNA, which enhances maternal levels of the cytokine interleukin-6 (IL-6)-and demonstrate a depression-like behavioral phenotype in adult offsprings. Adult offsprings additionally show deficits in cognition and hippocampal long-term potentiation (LTP) accompanied by disturbed proliferation of newborn cells in the dentate gyrus and compromised neuronal maturation and survival. The behavioral, neurogenic and functional deficiencies observed are associated with reduced hippocampal expression of vascular endothelial growth factor (VEGF)A-VEGFR2. IL-6-STAT3-dependent aberrant VEGFA-VEGFR2 signaling is proposed as neurobiological mechanism mediating the effects of MIA on the developing fetal brain and ensuing consequences in adulthood.

SUBMITTER: Khan D

PROVIDER: S-EPMC3944633 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Long-term effects of maternal immune activation on depression-like behavior in the mouse.

Khan D D Fernando P P Cicvaric A A Berger A A Pollak A A Monje F J FJ Pollak D D DD

Translational psychiatry 20140218

Depression is a debilitating mental disease affecting a large population worldwide, the pathophysiological mechanisms of which remain incompletely understood. Prenatal infection and associated activation of the maternal immune system (MIA) are prominently related to an increased risk for the development of several psychiatric disorders including schizophrenia and autism in the offsprings. However, the role of MIA in the etiology of depression and its neurobiological basis are insufficiently inve ...[more]

PMID: 24548878

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Project description:BackgroundFemale fetuses are more vulnerable to high levels of maternal glucocorticoids. We examined whether exposure to prenatal maternal depression, a condition associated with high glucocorticoids, carries greater risk for depression at 12 and 18 years in girls.MethodsOur sample comprised 7959 mothers and children from the Avon Longitudinal Study of Parents and Children following imputation for missing data. Maternal depression was assessed pre-and post-natally, and offspring depression at ages 12 and 18. We used logistic regression models to examine the relationship between exposure to prenatal and postnatal depression and offspring depression at 18 and 12 and interactions with gender.ResultsThere was an interaction between prenatal depression and gender (P=0.027) and between postnatal depression and gender (P=0.027) for offspring depression at 18. Following adjustment in pre-natally depressed mothers, the odds ratio for offspring depression at 18 was 1.55 (95% c.i. 1.03-2.34) for girls and 0.54 (0.23-1.26) for boys. In post-natally depressed mothers, the odds ratio for offspring depression at 18 was 1.15 (0.70-1.89) in girls and 3.13 (1.52-6.45) in boys. However there was no evidence for interaction between prenatal or postnatal depression and gender (P=0.559 and 0.780 respectively) for offspring depression at 12.LimitationsAs expected with this large cohort spanning over 18 years, there was loss-to-follow-up.ConclusionsThis is the first evidence in humans that increased vulnerability of female fetuses to maternal stress responses during pregnancy persists into adolescence. One explanation for gender differences emerging later is more depressive symptomatology is attributed to heritable risk at 12, whereas biological processes involved in brain development at 18 may be influenced by foetal programming. If replicated, this study has potential to help understand intergenerational transmission of depression, a leading cause of morbidity worldwide.

Project description:Infection during pregnancy can lead to activation of the maternal immune system and has been associated with an increased risk of having an offspring later diagnosed with a neurodevelopmental disorders (NDD) such as autism spectrum disorder (ASD) or schizophrenia (SZ). Most maternal immune activation (MIA) studies to date have been in rodents and usually involve the use of lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). However, since NDD are based on behavioral changes, a model of MIA in non-human primates could potentially provide data that helps illuminate complex behavioral and immune outputs in human NDD. In this study twenty-one pregnant rhesus macaques were either given three injections over 72 hours of poly I:C-LC, a double stranded RNA analog (viral mimic), or saline as a control. Injections were given near the end of the first trimester or near the end of the second trimester to determine if there were differences in immune output due to the timing of MIA.An additional three non-treated animals were used as controls. The offspring were followed until 4 years of age, with blood collected at the end of their first (year 1) and fourth (year 4) years to assess dynamic cellular immune function. Induced responses from peripheral immune cells were measured using multiplex assays.At one year of age, MIA exposed offspring displayed elevated production of innate inflammatory cytokines including: interleukin (IL)-1β, IL-6, IL-12p40, and tumor necrosis factor (TNF)α at baseline and following stimulation. At four years of age, the MIA exposed offspring continued to display elevated IL-1β, and there was also a pattern of an increased production of T-cell helper type (TH)-2 cytokines, IL-4 and IL-13. Throughout this time period, the offspring of MIA treated dams exhibited altered behavioral phenotypes including increased stereotyped behaviors. During the first two years, stereotyped behaviors were associated with innate cytokine production. Self-directed behaviors were associated with TH2 cytokine production at year 4. Data from this study suggests long-term behavioral and immune activation was present in offspring following MIA. This novel non-human primate model of MIA may provide a relevant clinically translational model to help further elucidate the role between immune dysfunction and complex behavioral outputs following MIA.

Project description:Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12-P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca(2+) for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca(2+) release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a presynaptic form of hippocampal t-LTD similar to that previously described at neocortical synapses during development.

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Long-term effects of maternal immune activation on depression-like behavior in the mouse.

Publications

Long-term effects of maternal immune activation on depression-like behavior in the mouse.

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