Maternal Immune Activation Causes Overgrowth of the Fetal Cerebral Cortex
RM Elliott, MP Anderson. Beth Israel Deaconess Medical Center, Boston, MA
Background: Maternal infection during fetal brain development has been implicated as an important factor in the development of autism and schizophrenia, but a definitive link between the maternal immune response and altered fetal brain development has not been demonstrated histopathologically. At an early age, autistic children display a significant increase in the thickness of the cortical mantle. The cause of this increase remains unknown, but recent evidence indicates the presence of maternal-fetal antibodies in autism. Other cases of autism have been associated with perinatal viral infection. We investigated whether activation of the maternal immune system might be the common factor that is sufficient to promote a disturbance of fetal brain development using an agent that mimics a maternal viral infection, polyriboinosinic-polyribocytidilic acid (polyI:C).
Design: Daily intraperitoneal injections of polyI:C (5 mg/kg) were performed on E10-E14 or E14-E18. Mouse pups were sacrificed on the first day of life (P1), and the brains were processed for routine histological analysis. Photomicrographs of hematoxylin and eosin stained sections were analyzed using ImageJ (NIH) software to determine cell density in layers I, II-III, IV-V, and VI of the S1H1 area of the cerebral cortex.
Results: E10-E14 mice (n=16) displayed increased cell densities in all cortical layers when compared to controls (n=15): 49% in layer I, 23% in layers II-III, 15% in layers IV-V, and 25% in layer VI (p<0.01). E14-E18 mice (n=16) showed similar increases in layers I, IV-V, and VI: 50%, 17%, and 26%, respectively (p<0.0001). In layers II-III, however, there was a larger increase of 47% (p<0.0001).
Conclusions: The results support our hypothesis that maternal immune activation alone, potentially caused by a variety of insults (e.g. infection, autoimmunity), during pregnancy is sufficient to disturb fetal brain development. In addition, the data suggest the timing of immune activation has layer-specific effects, providing a potential explanation for different behavioral disorders (e.g. autism, schizophrenia). This cortical overgrowth may promote the development of autism and/or schizophrenia through disturbances of the canonical cortical neural circuit architecture and function.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 219, Monday Morning