Immune activation during brain development in utero has been identified as a risk factor for the neurodevelopmental disorders autism and schizophrenia. We hypothesize that the effects maternal immune stimulation on brain and behavior may be exacerbated in genetic backgrounds that: 1) are sensitized to the consequences of immune stimulation, and 2) carry mutations or chromosomal rearrangements that confer risk for neurodevelopmental disorders. PTEN encodes a repressor of the PI3K signaling pathway and is involved in a variety of immune responses. Haploinsufficiency for PTEN is linked with both autoimmunity and impairments in cognition, including autism. Here we test whether a gene-environment interaction may exist between Pten and maternal immune activation. We show that stimulation of the maternal immune system using the viral ssRNA mimic and Tlr3 ligand Poly I:C leads to elevated rates of lethality in Pten haploinsufficient offspring as compared to wild type littermates. Using a relatively low dose of Poly I:C, we find that maternal immune activation acts as a modifier and exacerbates abnormal social behavior, anxiety, and sensorimotor gating phenotypes in Pten haploinsufficient offspring. In addition, brain size is modified in Pten haploinsufficient offspring of Poly I:C-treated dams. To investigate the molecular basis of the putative gene-environment interaction, we probed activation of the PI3K pathway, and find that AKT activation is elevated in the brains of embryos treated with Poly I:C in utero, a phenotype shared with Pten haploinsufficiency. This work shows how an environmental risk factor can lead to differential outcomes on autism-relevant phenotypes based on genetic background and points to dysregulation of the Pten-PI3K-Akt pathway as a mechanism contributing to the neurodevelopmental consequences of maternal immune activation.

Society for Neuroscience Abstract, 2009.