Maternal immune activation alters nonspatial information processing in the hippocampus of the adult offspring
Introduction
Schizophrenia is a major psychiatric disorder with a strong genetic contribution (Burmeister et al., 2008, Bertolino and Blasi, 2009). Nonetheless, epidemiologic evidence indicates that genetic factors alone cannot explain the pathogenesis. For example, the concordance for schizophrenia in monozygotic twins is approximately 48% (Gottesman, 1991). Furthermore, while the concordance between monozygotic twins who share a placenta is 60%, the concordance rate between such twins who do not share a placenta is only 10% (Davis et al., 1995, Patterson, 2007). These studies suggest the importance of the fetal environment. Supporting this idea, Mednick et al. (1988) reported that fetuses gestating during a viral epidemic are at elevated risk for developing schizophrenia. Subsequent prospective studies have shown that maternal infections of various types increase the risk for schizophrenia in the offspring 3- to 7-fold (reviewed by Patterson, 2009, Brown and Derkits, 2010).
Based on this evidence, several animal models of MIA have been established (reviewed by Meyer et al., 2009, Patterson, 2009). Among these, administration of the synthetic dsRNA, poly(I:C) can effectively induce MIA, resulting in offspring that display a variety of behaviors and neuropathologies that are consistent with those seen in schizophrenia patients (Meyer and Feldon, 2009, Patterson, 2009). Thus, this animal model is useful for investigating the pathophysiology of schizophrenia.
Clinical studies reveal an important role for dopamine (DA)-mediated signaling in the pathophysiology of schizophrenia. For example, drugs that increase DA release induce several aspects of schizophrenic psychosis in normal adults, and exacerbate psychotic symptoms in patients with schizophrenia (Angrist and Vankammen, 1984, Lieberman et al., 1987). Moreover, all drugs currently in widespread use for the treatment of schizophrenia block DA D2 receptors (Creese et al., 1976). Other studies suggest that there is a deficit in DA D1 receptor-mediated transmission in prefrontal areas of schizophrenic patients (Davis et al., 1991, Toda and Abi-Dargham, 2007). Indeed, imaging studies of patients reveal an increased D2 receptor density in the striatum (Weinberger and Laruelle, 2001) and a decreased D1 receptor density in the prefrontal cortex (Okubo et al., 1997).
Deficits in other cortical regions may also play a key role in the pathophysiology of schizophrenia. Among them, hippocampal abnormalities are commonly found (Heckers and Konradi, 2002). Lipska et al. (1993) suggested that the important variable is the developmental period during which the hippocampal damage takes place, because lesion of the adult rat hippocampus fails to produce schizophrenia-like behaviors, while hippocampal disruption in neonatal stages causes these behavioral alterations to emerge in adulthood. Most importantly in the present context, DA D1- and D2-like receptors are highly expressed in the hippocampus (Wamsley et al., 1989, Meador-Woodruff et al., 1994, Khan et al., 1998) and a reciprocal functional interaction between the DA system and the hippocampus has been suggested (Lisman and Grace, 2005). Together, these studies indicate that hippocampal dysfunction participates in the pathogenesis of schizophrenia.
Considering these findings, we used the poly(I:C) MIA mouse model to investigate the pathogenesis of schizophrenia-like behaviors. We focus on the hippocampal network and the influence of DA, conducting experiments at the synaptic as well as the behavioral level. The data suggest a link between synaptic dysfunction, DA and altered behavior.
Section snippets
Animals
Pregnant C57BL/6J mice were injected either i.v. with 5 mg/kg or i.p. with 20 mg/kg poly(I:C) potassium salt freshly dissolved in 0.9% sterile saline on E12.5. Both doses and routes of administration have been used to induce MIA and behaviors relevant to schizophrenia in adult offspring (Meyer et al., 2006; Smith et al., 2007). Control females were injected with the same volume of saline. The offspring were undisturbed until weaning on P21. Offspring were behaviorally tested from 6 to 11 weeks for
CA1 pyramidal neurons in the offspring of poly(I:C)-treated mothers display a reduced frequency and increased amplitude of mEPSCs
A number of studies indicate that the brains of schizophrenia patients exhibit a reduction in the volume of the hippocampus (Nelson et al., 1998, Heckers and Konradi, 2002). Although most studies on schizophrenia patients report no significant change in neuronal density in the hippocampus (Dwork, 1997, Harrison, 1999), many post-mortem studies have reported an abnormal expression of synaptic proteins, including synaptophysin (Eastwood and Harrison, 1995, Davidsson et al., 1999), synapsin I (
Reduced excitatory input on CA1 pyramidal neurons
Our electrophysiological studies demonstrate that the offspring of poly(I:C)-treated mothers display a decreased number, but enhanced efficacy, of excitatory synapses on CA1 pyramidal neurons. Synaptic abnormalities have also been observed in area CA3 in schizophrenia patients, including abnormal mRNA expression of presynaptic proteins (Harrison and Eastwood, 2001).
We do not observe a significant abnormality in the mIPSC amplitude or frequency in the offspring of poly(I:C)-treated animals.
Acknowledgments
We thank Prof. Erin M. Schuman (Caltech/Howard Hughes Medical Institute) and the HHMI for support in the electrophysiology and c-Fos experiments. The other experiments were supported by grants to P.H.P. from the National Institute of Mental Health and the McKnight Foundation. H.T.I. was supported by the Nakajima Foundation. S.E.P.S. was supported by the Autism Speaks Foundation. E.H. was supported by an NIH training grant.
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Present address: Departments of Neurology and Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA.