Mouse model of mental illness

 



Interleukin-6 mediates many of the effects of maternal immune activation on fetal brain development

            Stephen Smith, Paul H. Patterson

            Maternal infection by several different organisms have been implicated in the pathogenesis of schizophrenia.  Maternal influenza infection or maternal immune activation (MIA) with the double-stranded RNA, poly(I:C), or with bacterial lipopolysaccharide (LPS) in rodents causes behavioral, histological and transcriptional changes in adult offspring.  This indicates that MIA, rather than a specific pathogen, is responsible for the increased risk of mental illness in the offspring of mothers with infections during pregnancy.  In investigating the possibility that cytokines may mediate the effects of MIA, we find that the cytokine interleukin-6 (IL-6) is essential for the manifestation of  a variety of abnormalities in the adult offspring of poly(I:C)-treated mothers.  Pregnant mice given a single injection of IL-6 on E12.5 show deficits in pre-pulse inhibition of the acoustic startle response (PPI) as well as deficits in latent inhibition (LI).  Pregnant mice given an injection of poly(I:C) on E12.5 also show PPI, LI, exploratory and social interaction deficits, as previously reported.  Co-administration of an anti-IL-6 neutralizing antibody with the poly(I:C) prevents all of these deficits, while co-administration of anti-interferon-g or anti-IL-1b does not.  Anti-IL-6 also prevents maternal poly(I:C)-induced changes in gene expression in the adult frontal cortex.  Finally, maternal injection of poly(I:C) in IL-6 knockout mice does not cause behavioral deficits in the offspring.  Thus, IL-6 is necessary for MIA to produce autism- and schizophrenia-like behaviors that are manifested in the adult offspring.  Current research is exploring the site(s) of IL-6 action. 

Identifying the sites of interleukin-6 action following maternal immune activation

            Elaine Hsiao, Paul Patterson

            Maternal infection increases the risk for schizophrenia and autism in the offspring.  In rodents, maternal influenza infection or maternal immune activation (MIA) with the double-stranded RNA, poly(I:C) causes behavioral, histological and transcriptional changes in adult offspring that are consistent with those seen in schizophrenia and autism.  This indicates that MIA, rather than a specific pathogen, is responsible for the increased risk of mental illness in the offspring of mothers with infections during pregnancy.  In investigating the possibility that cytokines may mediate the effects of MIA, it was determined that the cytokine interleukin-6 (IL-6) is essential for the manifestation of a variety of abnormalities in the adult offspring of poly(I:C)-treated mothers. Therefore, localizing the site of IL-6 action may illuminate the anatomical and molecular pathways through which MIA alters fetal brain development. Towards that end, experiments are underway to identify the sites of IL-6 receptor activation as well as the tissues where genes regulated by IL-6 are being altered following MIA. The candidate target areas are the maternal immune system, the placenta and the fetal brain.

Maternal influenza infection alters fetal brain development

Limin Shi, Doris Tse1, Paul H. Patterson

Epidemiological studies have shown that maternal infection can increase the risk for mental illness in the offspring. In a mouse model of maternal respiratory infection with influenza virus, the adult offspring display striking behavioral, pharmacological and histological abnormalities. In addition to a spatially localized loss of Purkinje cells that is very similar to a common cerebellar pathology in autism, we find delayed migration of granule cells (GCs) in lobules VI and VII. During development, GCs are born in the external granular layer (EGL) and migrate through the molecular layer (ML) to their final position in the internal granular layer (IGL).  On P17, a time at which the EGL is disappearing in control mice, the EGL is significantly thicker in the offspring of infected mothers. This effect is most pronounced in lobules VI and VII, consistent with the localized deficit in PCs. The abnormally persistent EGL is eventually lost, however, as Nissl staining in adult animals reveals the normal absence of an EGL in both control and exposed offspring. To determine if the thicker EGL is due to a migrational delay, BrdU was injected at P11 to label newly generated GCs, and the mice sacrificed at P17.  We find significantly more BrdU+ GCs in the ML of lobule VII of exposed mice, suggesting a spatially localized migrational delay in exposed animals. No GCs are found in the ML of adult animals, however.. These findings in the mouse model are relevant to the pathology and behavioral abnormalities that have been linked to cerebellar pathology in autism and schizophrenia.

            1UC Riverside student

Interaction between genes and environment in a mouse model of mental illness

Catherine Bregere, Paul H. Patterson

Although it is recognized that both environmental and genetic factors are involved in the pathogenesis of autism and schizophrenia, their respective contributions to these disorders have been investigated independently. It is now possible to model an environmental risk factor, which has both face and construct validity for these disorders, and apply it to mouse models of several newly identified candidate genes, and study possible synergistic interactions. The environmental risk factor model involves maternal immune activation (MIA), using respiratory infection or injection of the viral mimic, poly(I:C). The offspring of MIA mice display behaviors and neuropathologies reminiscent of autism and schizophrenia. We have now initiated a study to assess whether mutant mice carrying a candidate gene are more vulnerable to MIA. Disrupted in schizophrenia-1 (DISC1) is a gene that is linked to mental illness, and several different lines of mice with mutant DISC1 display behavioral deficits consistent with schizophrenia. Preliminary evidence from mating wildtype female mice with heterozygous DISC1 males suggests that heterozygous DISC1 fetuses display increased sensitivity to polyIC. Additional mutant mouse lines relevant to mental diseases, including urokinase-type plasminogen activator receptor (uPAR) knockout mice will be similarly evaluated in the near future.

Information processing in the hippocampus of the offspring of immune-activated mothers

Hiroshi Ito, Stephen Smith

Maternal immune activation by injection of the dsRNA, poly(I:C), causes the offspring to display a series of behavioral abnormalities that are consistent with those seen in schizophrenia and autism. Several of these behaviors, including increased responses to low doses of amphetamine, as well as disrupted latent inhibition, suggest altered function of hippocampal and dopamine systems.  To examine this possibility, we made hippocampal slices from adult mice born to control or immune-activated mothers, and measured the electrophysiological responses of CA1 pyramidal neurons. The offspring of poly(I:C)-treated mice show increased amplitude and decreased frequency of spontaneous miniature excitatory post-synaptic currents, suggesting abnormal synaptic structure or function. Dopamine sensitivity in CA1 is of interest because dopamine is known to depress excitatory responses at temporoammonic-CA1 synapses. Compared to controls, we find that dopamine-induced excitatory depression is significantly larger in the slices from offspring of poly(I:C)-treated mothers, suggesting higher sensitivity to dopamine. Taken together, our physiological data suggest that the offspring of poly(I:C)-treated mothers exhibit abnormal information processing in the hippocampus.

Maternal immune activation impairs extinction of the conditioned eyeblink response in the adult offspring

Ka Hung Lee1, Stephen Smith, Soyun Kim1, Paul H. Patterson and Richard F. Thompson1

We are investigating classical eyeblink conditioning, a behavior that is abnormal in autistic subjects, in the adult offspring of poly(I:C)-injected mice. Pregnant mice are injected polyI:C or saline on embryonic day 12.5, and adult offspring are tested in a delay eyeblink conditioning paradigm. Compared to saline group, the offspring of the poly(I:C)-activated mothers show impaired extinction of the conditioned response. Auditory brainstem responses and tail-flick latency are similar in both groups, indicating normal auditory and somatosensory functions. The impaired extinction in poly(I:C) group suggests that perseverative motor behavior, a characteristic of autism, is induced in the offspring by maternal immune activation.

1University of Southern California

The effect of maternal immune activation on behavioral development of mouse offspring

Natalia Malkova, Paul H. Patterson

We are investigating the neurobehavioral development of mouse pups born to mothers whose immune systems were activated at mid-gestation. Tests include the rate of ultrasonic vocalizations, which is important for mother–infant social interaction, maturation status of neuromotor reflexes, and neurogenesis. We find that injection of double stranded RNA (poly(I:C)), which evokes an inflammatory response in the mother similar to that induced by influenza virus, alters the behavior of the offspring. Compared to controls, 10 day old C57BL/6J pups born to mothers given poly(I:C) on E12.5 have lower rates of ultrasound calling when separated from their mothers. Analysis of temporal organization of pup ultrasonic vocalizations shows that, compared to controls, pups born to poly(I:C)-treated mothers emit more single calls than calls in bouts. We also monitored developing motor reflexes such as negative geotaxis, righting and grasping, and used body weight as an indicator of general health. No difference is found in the physical abilities and general health between the control and experimental groups. Thus, the deficit in the social behavior of pups born to mothers with an activated immune system is not due to a delay in physical development. The absence of detectable differences in maternal responsiveness towards the pups also suggests that the fewer distress calls emitted by pups are the result of a reduced sensitivity to isolation.

It is known that FOXP2 is a genetic factor in the pathogenesis of speech-language disorder and Foxp2 knockout mice have deficit in ultrasonic vocalization. Therefore, studies are in progress to analyze whether FOXP2 expression is affected in the pups born to mothers whose immune systems were activated.

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This page last updated August, 2008 by C. Patterson.