Perinatal inflammatory cytokine challenge results in distinct neurobehavioral alterations in rats: implication in psychiatric disorders of developmental origin

Tohmi, Manavu; Tsuda, Noriko; Watanabe, Yuichiro; Kakita, Akiyoshi; Nawa, Hiroyuki

doi:10.1016/j.neures.2004.05.010

Cited by 70 publications

(46 citation statements)

References 55 publications

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“…In agreement with our previous report (Borrell et al, 2002), this study demonstrates that a prenatal immune challenge, provoked by LPS exposure during gestation, disrupts PPI in adult life, and further supports the critical influence of perinatal events on information processing at an adult age (Ellenbroek et al, 1998;Shi et al, 2003;Tohmi et al, 2004).…”

Section: Discussion Altered Dopaminergic Neurotransmission In Ppi-defsupporting

confidence: 92%

“…In addition, an in vitro study shows that the inflammatory cytokines TNF-a, IL-1b, and IL-6 can inhibit the development of dendrites in embryonic cortical neurons, consistent with the neuropathology of schizophrenia (Gilmore et al, 2004). In rats, neonatal administration of proinflammatory cytokines (Tohmi et al, 2004) or leukemia inhibitory factors induce future psychobehavioral and/or cognitive impairments. Thus, it is likely that the maternal immune response, particularly involving the proinflammatory cytokines, interferes with normal fetal brain development and that maternal infections during pregnancy are potential risk factors for schizophrenia (Gilmore et al, 2004;Nawa and Takei, 2006).…”

Section: Introductionmentioning

confidence: 69%

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Neurobehavioral and Immunological Consequences of Prenatal Immune Activation in Rats. Influence of Antipsychotics

Romero

Ali

Molina‐Holgado

et al. 2006

Neuropsychopharmacol

129

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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.

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Section: Discussion Altered Dopaminergic Neurotransmission In Ppi-defsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 69%

Neurobehavioral and Immunological Consequences of Prenatal Immune Activation in Rats. Influence of Antipsychotics

Romero

Ali

Molina‐Holgado

et al. 2006

Neuropsychopharmacol

129

View full text Add to dashboard Cite

show abstract

“…30,40 However, we did not detect any neurobehavioral influences of control proteins (cytochrome c and albumin) in the in vivo experimental paradigm. 40,77,78 In conclusion, NRG1 is one of the key neurotrophic factors that have crucial impact on dopaminergic development and its neuropathology. We hope that this model established with NRG1 will facilitate the validation of both neurodevelopmental and dopaminergic hypotheses of schizophrenia.…”

Section: -70mentioning

confidence: 98%

“…77 Among many factors examined, neonatal treatment only with epidermal growth factor, interleukin-1 and NRG1 produce the long-lasting behavioral impairments that are implicated in schizophrenia models. 40,66,78 Interestingly, these factors have a common neurotrophic activity on midbrain dopaminergic neurons. 30,40 However, we did not detect any neurobehavioral influences of control proteins (cytochrome c and albumin) in the in vivo experimental paradigm.…”

Section: -70mentioning

confidence: 99%

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

et al. 2010

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Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis.

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“…Thus, intense variations in the levels of inflammatory cytokines in the fetal environment may therefore adversely affect the development of the nervous system, and contribute to the development of future psychobehavioral and/or cognitive impairments. [14][15][16][17][18][19][20][21] The pattern of immune development can also be modulated by maternal immune events during gestation 22 and indeed, it has been suggested that postnatal immune responses are programmed in utero. 23 Systemic administration of lipopolysaccharide (LPS) is a widely accepted model for emulating immune activation and it is known to release peripheral immunoregulatory cytokines 24 and also to stimulate cytokine expression in the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: implications for the etiopathology of schizophrenia

et al. 2008

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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.

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Perinatal inflammatory cytokine challenge results in distinct neurobehavioral alterations in rats: implication in psychiatric disorders of developmental origin

Cited by 70 publications

References 55 publications

Neurobehavioral and Immunological Consequences of Prenatal Immune Activation in Rats. Influence of Antipsychotics

Neurobehavioral and Immunological Consequences of Prenatal Immune Activation in Rats. Influence of Antipsychotics

Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia

Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: implications for the etiopathology of schizophrenia

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