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ICOSR 2009—Investigating Infectious Etiology in Schizophrenia

As part of our ongoing coverage of the 2009 International Congress on Schizophrenia Research (ICOSR), 28 March to 1 April 2009, in San Diego, California, we bring you session summaries from some of the Young Investigator travel award winners. We are grateful for this summary by Eric Epping of the University of Iowa, who in fact was a travel awardee at the 2007 meeting and was generous enough to file a report this year as well!

20 April 2009. Recent findings in understanding the connection between infections in utero and the risk of developing schizophrenia were the focus of the symposium “New Evidence for an Infectious Etiology of Schizophrenia” on Tuesday, 31 March, at the ICOSR, chaired by Alan Brown from Columbia University in New York. Many studies have demonstrated a link between maternal infection during pregnancy and an increased risk of schizophrenia in the exposed offspring. Clinical and basic science researchers presented results of their efforts to identify the organisms and mechanisms responsible, as well as the effects on brain structures, functions, and neurocognition in schizophrenia patients and animal models. The symposium exemplifies the importance of integrating studies in humans and animal models to better understand the pathophysiology of schizophrenia.

Mark Weiser from Sheba Medical Center in Tel Aviv, Israel, presented data investigating the potential link between childhood CNS infections and the subsequent development of psychosis. Using the anonymous Israeli Psychiatric Hospital Case Registry from seven hospitals, 3,599 children hospitalized for a CNS infection (mean age 3.4 years) were compared to a group of 6,371 children hospitalized for gastroenteritis (mean age 2.7 years) to determine if the CNS infection group developed schizophrenia at a higher rate. With a mean follow-up of 25 years, no significant association was found between the two groups. A post-hoc analysis of dividing the CNS infection group into viral versus bacterial infections showed no differences in schizophrenia risk; however, hospitalization at a younger age did show an increased risk, with the highest risk from hospitalization between ages 2 and 5 for bacterial meningitis.

Kuei Tseng, currently at Rosalind Franklin University of Medical Science at the Chicago Medical School, gave a talk on studies initiated when he was in Patricio O’Donnell’s lab at the University of Maryland. Using rodent models, he described the effect of neonatal disruption of ventral hippocampus resulting in alterations of dopamine D2 receptor mediated activation of fast-spiking GABA interneurons (FSIs) in the prefrontal cortex (PFC). The characteristic D2-dependent facilitation of prefrontal FSI excitability becomes apparent only in post-adolescent rats. Disruption of normal PFC interneuron activity was observed in two different hippocampal disconnection models: the neonatal ventral hippocampal lesion (NVHL) model produced by injection of ibotenic acid into the hippocampus, or injection of lipopolysaccharide (LPS) into the hippocampus, with both induced at about one week of postnatal age. If LPS is injected into the hippocampus of neonatal rats, cytokine signaling is increased in the brain and prepulse inhibition of the acoustic startle response is disrupted when the rats reach adult age. While baseline activity of fast-spiking interneuron function is intact in these animals, D2 dependent facilitation of this activity in the PFC is disrupted, but this is observed only in older animals tested after 65 days of age. This work shows that neonatal disruption of the ventral hippocampus, including an infectious etiology, can result in synaptic abnormalities in the PFC that are expressed during the peri-adolescent transition to adulthood, consistent with a delayed onset of positive and cognitive symptoms in schizophrenia.

Symposium chair Alan Brown described the results of studies on the effects of prenatal infections on neuropsychological functioning and brain volumes in schizophrenia. Previous studies by another group had identified potential links between development of schizophrenia and in utero infections with herpes simplex viruses (HSV1 and 2), and cytomegalovirus (CMV), or elevated maternal levels of interleukin-8 (IL-8), an inflammatory cytokine that is increased by CNS infection. Using a sample of 26 schizophrenia cases and 25 controls from California (in collaboration with Kaiser Permanente) with available maternal serum specimens during pregnancy, in utero viral exposure or IL-8 levels were associated with differences in cognitive performance and brain structure volumes in adult schizophrenia patients. HSV1 exposure was associated with worse executive functioning (Wisconsin card sort test), verbal memory performance (California verbal learning test, CVLT), and information processing (symbol search). HSV2 exposure was associated with increased deficits in working memory (digit span and N-back test), verbal memory (CVLT), and a slight reduction in motor function. CMV exposure was not associated with any statistically significant differences, but trends toward worse performance were observed for executive functioning, attention, memory, and information processing.

Associations between viral exposure and brain volume measures were also reported. HSV2 exposure was associated with significantly decreased right thalamus volumes, and trends toward significance for decreased left thalamus and putamen volumes in cases exposed to the virus. Significant reductions in thalamic volumes, and an increase in sulcal CSF volumes were associated with CMV exposure. The thalamic findings are particularly interesting as smaller volumes are associated with more severe symptoms in schizophrenia. Increased IL-8 levels were associated with larger ventricular CSF volume, smaller left entorhinal cortex, left putamen, right caudate, and right superior temporal gyrus. A new study in progress will use a cohort from Finland to further explore the effects of in utero infection on schizophrenia and other psychiatric disorders. The data presented here indicate differential effects of in utero viral exposure on schizophrenia phenotypes.

Paul Patterson from the California Institute of Technology in Pasadena concluded the session with his talk on maternal infection and cytokines in schizophrenia and autism. His lab is working to address three questions regarding the reported immune dysregulation in the brain and psychiatric illness: 1) how is it established, 2) how is it maintained, and 3) what are the effects on behavior? He presented results from experiments in a mouse model wherein pregnant dams are injected with the double stranded RNA polyI:C, which induces cytokine production similar to that induced by viral infections. mRNA for interleukin-6 (IL-6) is increased in the placenta and fetal brain following maternal polyI:C injection, which subsequently activates expression of the suppressor of cytokine signaling 3 (SOCS3) gene in these tissues as well. Injection of polyI:C or IL-6 into pregnant mothers also results in behavioral changes in the offspring consistent with schizophrenia phenotypes. IL-6 is the critical molecule in this pathway, as co-injecting IL-6 antibodies with polyI:C in pregnant animals blocks the biological and offspring behavioral effects of polyI:C, similar to the results of injecting polyI:C into a mouse that has a knockout of the IL-6 gene.

Additional experiments have begun to elucidate the mechanistic effects of polyI:C and IL-6 activation. Erk in the mitogen activated protein (MAP) kinase pathway on the fetal side of the placenta is activated, as is STAT (signal transduction and activator of transcription) protein phosphorylation. Preliminary observations suggest that maternal macrophages are increased in the umbilical cord, and in the fetus within 12 hours of polyI:C injection. Patterson also mentioned that studies are underway using the polyI:C model in non-human primates. The rodent results indicate that IL-6 is an important molecule linking in utero stresses and increased risk of schizophrenia, with evidence that not only infections, but also maternal behavioral stress and malnutrition increase IL-6 levels. It remains to be determined if the changes in IL-6 expression are enduring, as the results presented here measure the effect within the first day after polyI:C injection. Another question at the end of the symposium was in regard to the link between IL-6 and IL-8. It was noted that IL-6 can induce IL-8 expression, but more evidence is needed to characterize this relationship in the context of schizophrenia.—Eric A. Epping.