Prenatal Immune Challenge Disrupts Sensorimotor Gating in Adult Rats Implications for the Etiopathogenesis of Schizophrenia

Abstract

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 (Braff et al. 1978;Kumari et al. 1999). A well-established sensorimotor gating paradigm is the prepulse inhibition (PPI) of the startle response. PPI refers to the reduction in startle reactivity toward an intense pulse stimulus when it is shortly preceded by a weak prepulse stimulus (Hoffman and Ison 1980). It is thought that the prepulse response activates an inhibitory process that attenuates or "gates" the startle response. Because identical stimulus parameters can be used for animal and human studies, it is considered that animal models of PPI disruption represent a promising way to study the neural mechanisms underlying sensorimotor gating dysfunction (Swerdlow et al. 1994(Swerdlow et al. , 1999Swerdlow and Geyer 1998) and as a screening test for potential antipsychotics (Swerdlow et al. 1994;Depoortere et al. 1997). In fact, antipsychotics remove PPI deficits in schizophrenic patients (Kumari et al. 1999;Weike et al. 2000). Nevertheless, it must be taken into consideration that deficiency of PPI has been reported in other selected neuropsychiatric disorders where inability to inhibit movements is involved (Huntington's disease (Swerdlow et al. 1995 Tourette's syndrome (Castellanos et al. 1996)), where inability to control attentional and cognitive processes is involved (obsessive-compulsive disorder (Swerdlow et al. 1993)), or where anxiety and exaggerated startle occur (posttraumatic stress disorder (Grillon et al. 1996)). The focus of schizophrenia research has been turning from studies of structural and functional brain abnormalities to an increasing emphasis on possible etiologic factors. Neurodevelopmental theories of schizophrenia postulate that the psychopathology of schizophrenia may derive from alterations of brain organization secondary to defective ontogenesis (Weinberger 1996;Raedler et al. 1998). A causal relationship pertaining to disturbed brain ontogenesis and schizophrenia comes from epidemiological studies that have identified several risk factors that, acting during pregnancy, increase the incidence of the disease in offspring. Maternal infection with influenza virus in the second trimester of preg...

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.…”

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…Hence, even though abnormalities in microglia functions can occur following prenatal immune challenge (Borrell et al, 2002;Juckel et al, 2011;Van den Eynde et al, 2014;Zhu et al, 2014), our findings suggest that such changes are not a prerequisite for synaptic deficits to occur, at least within the dorsal and ventral hippocampus. This interpretation is consistent with the findings derived from disease models of chronic neurodegeneration, suggesting that microglia do not play an active role in either synaptic stripping or synapse degeneration in the hippocampal formation (Perry and O'Connor, 2010;Sisková et al, 2009).…”

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

“…14 Furthermore, schizophrenia-like abnormalities have also been observed in rats prenatally exposed to the bacterial endotoxin LPS. 13 Given that exposure with PolyI:C, LPS and influenza virus are all capable of stimulating pro-inflammatory cytokine responses in the maternal host, 9,26,27 the findings from different prenatal infection and/or inflammation models in rodents readily support the hypothesis that enhanced expression of pro-inflammatory cytokines at the maternal-fetal interface may critically underlie the deleterious effects of prenatal infection and/or inflammation on normal brain and behavioral development. Here, we went on to show that this association might be specifically related to the balance between pro-and anti-inflammatory cytokine classes in prenatal life.…”

“…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.…”