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

Abstract

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.

Impact of Prenatal Immune System Disturbances on Brain Development

“…While the PolyI:C challenge during early-gestation (gestational day 6, GD6) resulted in a high incidence of abortion, a viral-like infection during mid-gestation (GD9) confirmed the precipitation of psychosis-related symptoms in the adult offspring, in line with previous findings by other groups (Borrell et al, 2002;Shi et al, 2003;Zuckerman et al, 2003;Zuckerman and Weiner, 2005;Ozawa et al, 2006;Romero et al, 2007). A late-gestational (GD17) immune challenge resulted in a behavioural phenotype characterized by cognitive impairments, elevation of fetal IL6, IL10, and TNFα, enhanced apoptosis in the dentate gyrus, as well as a decline in Reelinpositive cells in juvenile brains (Fig.…”

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

“…12 They may also be critically involved in the precipitation of the long-term behavioral, cognitive and pharmacological consequences of prenatal immune challenge as shown in vivo. [13][14][15][16][17][18][19][20] In contrast, very little is known about the putative roles of anti-inflammatory cytokines in the association between prenatal inflammation and the emergence of brain and behavioral abnormalities. One of the best characterized anti-inflammatory cytokine is IL-10.…”

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento

“…Male offspring of maternal immune activation showed an increase in tumour necrosis factor α (TNF) throughout their lifespan, as seen in schizophrenia 128,132,133 . Antipsychotics have been shown to reverse the effects of maternal immune activation on the behavioural and serum cytokine levels 134,135 . Maternal infection of rodents with influenza virus has led to deficits in social interaction and acoustic PPI in the offspring 136 .…”