 fetal brain development, dual first authors of the second paper, Urs Meyer and Myriel Nyffeler used a mouse model of acute inflammation during pregnancy that results in behavioral deficits in the offspring (Shi et al., 2003; Meyer et al., 2005). In this model, injecting pregnant mice with a synthetic analog of double-stranded RNA (polyI:C) elicits a strong but transient inflammatory response, and allows studies on the effects on offspring through postnatal life.
By dosing at two different gestational stages, the investigators found distinct patterns of psychopathological outcomes, cytokine production, and brain neuropathology as a result of the timing of inflammation. When they treated with polyI:C at gestational day 9 (thought to be in the vicinity of the first-to-second trimester transition in humans: Kaufman, MH  The atlas of mouse development. London: Academic), the offspring showed significantly reduced exploratory behavior in an open field test as young adolescents. Offspring of mothers who were dosed at day 17 (equivalent to human second-to-third trimester transition) also showed a decrease in exploratory behavior in an open field, but it was much smaller and not statistically significant. The later-treated animals did show significant behavioral changes by a different measure, a reversal-of-choice task, where they took longer to learn the new choice. This perseverative behavior is proposed to model the lack of behavioral flexibility seen in schizophrenia and several other disorders, including autism and obsessive-compulsive disorder.
The neuropathological correlates of these behavioral changes were different in the offspring from earlier or later-treated mouse dams. Gross brain morphology was unaltered, but a closer look showed that the mice that were exposed on P9, and thus experienced inflammation at mid-gestation, had reduced reelin-positive cells in the hippocampus. The mice that experienced inflammation later showed reductions in reelin-expressing cells that were not as severe. Both groups had a loss of newly born neurons in the dentate gyrus of the hippocampus, but only the mice treated later in gestation displayed significantly elevated levels of caspase activation and apoptosis of neurons. The mice also showed different patterns of maternal and fetal production of proinflammatory and anti-inflammatory cytokines, depending on the timing of polyI:C injection.
These results suggest that the same inflammatory stimulus, when present at different gestational stages, can interfere with distinct developmental pathways via stimulation of varying cytokine profiles. If these results translate to humans, then timing of infection and the cytokines induced should be a critical determinant of the type of pathology that shows up in adulthood. This jibes with the current epidemiological study, and previous ones using the same group of patients (Brown et al., 2001; Brown et al., 2004), that link the risk for schizophrenia to infections occurring in a window of vulnerability in early to mid-pregnancy.—Pat McCaffrey.
Babulas V, Factor-Litvak P, Goetz R, Schaefer CA, Brown AS. Prenatal exposure to maternal genital and reproductive infections and adult schizophrenia. Am J Psychiatry. 2006 May;163(5):927-9. Abstract
Meyer U, Nyffeler M, Engler A, Urwyler A, Schedlowski M, Knuesel I, Yee BK, Feldon J. The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology. J Neurosci. 2006 May 3;26(18):4752-62. Abstract