Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia (original) (raw)
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Brain, Behaviour and Immunity, 2017
Maternal exposure to infectious agents during gestation has been identified as a significant risk factor for schizophrenia. Using a mouse model, past work has demonstrated that the gestational timing of the immune-activating event can impact the behavioural phenotype and expression of dopaminergic and glutamatergic neurotransmission markers in the offspring. In order to determine the inter-species generality of this effect to rats, another commonly used model species, the current study investigated the impact of a viral mimetic Poly (I:C) at either an early (gestational day 10) or late (gestational day 19) time-point on schizophrenia-related behaviour and neurotransmitter receptor expression in rat offspring. Exposure to Poly (I:C) in late, but not early, gestation resulted in transient impairments in working memory. In addition, male rats exposed to maternal immune activation (MIA) in either early or late gestation exhibited sensorimotor gating deficits. Conversely, neither early nor late MIA exposure altered locomotor responses to MK-801 or amphetamine. In addition, increased dopamine 1 receptor mRNA levels were found in the nucleus accumbens of male rats exposed to early gestational MIA. The findings from this study diverge somewhat from previous findings in mice with MIA exposure, which were often found to exhibit a more comprehensive spectrum of schizophrenia-like phenotypes in both males and females, indicating potential differences in the neurodevelopmental vulnerability to MIA exposure in the rat with regards to schizophrenia related changes.
Journal of Neuroimmune Pharmacology
Background Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions. Methods In vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring. Results MIA-treated offspring showed disrupted recog...
Molecular Neurobiology, 2020
Schizophrenia is a complex neuropsychiatric disorder, influenced by a combined action of genes and environmental factors. The neurodevelopmental origin is one of the most widely recognized etiological models of this heterogeneous disorder. Environmental factors, especially infections during gestation, appear to be a major risk determinant of neurodevelopmental basis of schizophrenia. Prenatal infection may cause maternal immune activation (MIA) and enhance risk of schizophrenia in the offspring. However, the precise mechanistic basis through which MIA causes long-lasting schizophrenia-like behavioral deficits in offspring remains inadequately understood. Herein, we aimed to delineate whether prenatal infection-induced MIA causes schizophrenia-like behaviors through its long-lasting effects on immune-inflammatory and apoptotic pathways, oxidative stress toxicity, and antioxidant defenses in the brain of offspring. Sprague-Dawley rats were divided into three groups (n = 15/group) and were injected with poly (I:C), LPS, and saline at gestational day (GD)-12. Except IL-1β, plasma levels of IL-6, TNF-α, and IL-17A assessed after 24 h were significantly elevated in both the poly (I:C)-and LPS-treated pregnant rats, indicating MIA. The rats born to dams treated with poly (I:C) and LPS displayed increased anxiety-like behaviors and significant deficits in social behaviors. Furthermore, the hippocampus of the offspring rats of both the poly (I:C)-and LPS-treated groups showed increased signs of lipid peroxidation, diminished total antioxidant content, and differentially upregulated expression of inflammatory (TNFα, IL6, and IL1β), and apoptotic (Bax, Cas3, and Cas9) genes but decreased expression of neuroprotective (BDNF and Bcl2) genes. The results suggest long-standing effects of prenatal infections on schizophrenia-like behavioral deficits, which are mediated by immune-inflammatory and apoptotic pathways, increased oxidative stress toxicity, and lowered antioxidant and neuroprotective defenses. The findings suggest that prenatal infections may underpin neurodevelopmental aberrations and neuroprogression and subsequently schizophrenia-like symptoms.
Molecular Psychiatry, 2010
It has been hypothesized that the maternal immune response to infection may influence fetal brain development and lead to schizophrenia. Animal experimentation has supported this notion by demonstrating altered sensorimotor gating (prepulse inhibition, PPI) in adult rats prenatally exposed to an immune challenge. In the present study, pregnant rats were exposed to the bacterial endotoxin lipopolysaccharide (LPS) throughout gestation and the offspring were examined by evaluating the PPI, dopaminergic function, brain protein expression and cytokine serum levels from weaning to late adulthood. Prenatal LPS exposure induced a deficit in PPI that emerged at 'puberty' and that persisted throughout adult life. This prenatal insult caused age-specific changes in accumbal dopamine levels and in synaptophysin expression in the frontal cortex. Moreover, serum cytokine levels were altered in an age-and cytokinedependent manner. Here we show that prenatal LPS administration throughout pregnancy causes maturation-dependent PPI deficits and age-dependent alterations in dopamine activity, as well as in synaptophysin expression and cytokine levels.
Brazilian journal of medical and biological research = Revista brasileira de pesquisas médicas e biológicas / Sociedade Brasileira de Biofísica ... [et al.], 2012
Prenatal immune challenge (PIC) in pregnant rodents produces offspring with abnormalities in behavior, histology, and gene expression that are reminiscent of schizophrenia and autism. Based on this, the goal of this article was to review the main contributions of PIC models, especially the one using the viral-mimetic particle polyriboinosinic-polyribocytidylic acid (poly-I:C), to the understanding of the etiology, biological basis and treatment of schizophrenia. This systematic review consisted of a search of available web databases (PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge) for original studies published in the last 10 years (May 2001 to October 2011) concerning animal models of PIC, focusing on those using poly-I:C. The results showed that the PIC model with poly-I:C is able to mimic the prodrome and both the positive and negative/cognitive dimensions of schizophrenia, depending on the specific gestation time window of the immune challenge. The model resembles th...
The Journal of Neuroscience, 2013
It has been suggested that severe adverse life events during pregnancy increase the risk of schizophrenia in the offspring. The serotonin 5-HT 2A and the metabotropic glutamate 2 (mGlu2) receptors both have been the target of considerable attention regarding schizophrenia and antipsychotic drug development. We tested the effects of maternal variable stress during pregnancy on expression and behavioral function of these two receptors in mice. Prenatal stress increased 5-HT 2A and decreased mGlu2 expression in frontal cortex, a brain region involved in perception, cognition, and mood. This pattern of expression of 5-HT 2A and mGlu2 receptors was consistent with behavioral alterations, including increased head-twitch response to the hallucinogenic 5-HT 2A agonist DOI [1-(2,5-dimethoxy-4-iodophenyl)-2aminopropane] and decreased mGlu2-dependent antipsychotic-like effect of the mGlu2/3 agonist LY379268 (1R,4R,5S,6R-2-oxa-4aminobicyclo[3.1.0]hexane-4,6-dicarboxylate) in adult, but not prepubertal, mice born to stressed mothers during pregnancy. Cross-fostering studies determined that these alterations were not attributable to effects of prenatal stress on maternal care. Additionally, a similar pattern of biochemical and behavioral changes were observed in mice born to mothers injected with polyinosinic:polycytidylic acid [poly(I:C)] during pregnancy as a model of prenatal immune activation. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for schizophrenia and other psychiatric disorders.
Neuropsychopharmacology, 2007
Increasing evidence suggests that pre-or perinatal events that influence the immune system contribute to the development of behavioral or neuropsychiatric disorders. For instance, exposure of pregnant rats to the bacterial endotoxin lipopolysaccharide (LPS) disrupts sensorimotor information processing, as assessed by the prepulse inhibition test (PPI), and also the immune function in adult offspring, which might be of particular relevance as regards schizophrenia. However, the consequences of maternal LPS exposure during pregnancy on synaptic functioning in adult offspring and, more importantly, the therapeutic opportunity to re-establish PPI and immune function have still to be demonstrated. In this work, we analyzed the consequences of prenatal LPS exposure on dopaminergic neurotransmission and presynaptic markers in adult brain areas related to PPI circuitry. In addition, we tested whether oral treatment with the typical antipsychotic drug haloperidol (HAL) could reinstate PPI performances and cytokine serum levels in six-month-old male rats with prenatal LPS exposure. Both sensory information processing deficits and immune anomalies induced by prenatal exposure to LPS were accompanied by changes in dopaminergic neurotransmission and synaptophysin expression. It is important to note that PPI disruption and serum increases in cytokines induced by prenatal LPS exposure were both reversed by HAL. Taken together, these results demonstrate the critical influence of prenatal immune events on the functioning of adult nervous and immune systems, in association with the putative role of the immune system in the development of behavior relevant to schizophrenia.
Schizophrenia Research, 2015
Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of proinflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brainderived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or *
Neuropsychopharmacology, 2002
Increasing evidence associates schizophrenia with prenatal exposure to infection. Impaired ability to "gate out" sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) of the acoustic startle reflex. We analyzed the effect of a prenatal immune challenge-peripheral administration of bacterial endotoxin lipopolysaccharide (LPS) to pregnant female rats-upon PPI and immune function in adult offspring. Prenatal LPS treatment disrupted PPI which was reversed by antipsychotics. Serum levels of interleukin-2 and interleukin-6 were increased. In addition, histopathological features in brain areas related with PPI circuitry were observed. These results illustrate the critical influence of prenatal immune events upon adult CNS functioning in association with the putative role of the immune system in the etiopathogenesis of schizophrenia.
Neuroscience, 2006
Prenatal exposures to a variety of infections have been associated with an increased incidence of schizophrenia. We have reported that a single injection of the synthetic cytokine releaser PolyI:C to pregnant mice produced offspring that exhibited multiple schizophrenia-related behavioral deficits in adulthood. Here, we characterized the effect of maternal inflammation during fetal brain development on adult limbic morphology and expression of GABA A-receptors. The PolyI:C treatment did not induce morphological abnormalities but resulted in a significant increase in GABA A receptor subunit ␣2 immunoreactivity (IR) in the ventral dentate gyrus and basolateral amygdala in adult treated compared to control subjects. Correlative analyses between the a2 subunit IR in the ventral dentate gyrus and the performance in the prepulse inhibition paradigm revealed a significant correlation in controls that was however absent in the pathological condition. These results suggest that prenatal immune activation-induced disturbances of early brain development result in profound alterations in the limbic expression of GABA A receptors that may underlie the schizophrenia-related behavioral deficits in the adult mice.