The GABA(A) receptor ?3 subunit gene GABRB3 has been strongly implicated in the pervasive developmental disorders (PDD). GABRB3 lies within chromosome 15q11-13, and anomalies in this region are associated with Rett syndrome, Prader-Willi syndrome, Angelman Syndrome, and are the single most frequent cytogenetic abnormality found in the autism spectrum disorders (ASD). It has recently been recognized that peripheral GABA(A) receptors are involved in immune cell regulation and that activation of GABA(A) receptors can attenuate tissue inflammation. Maternal inflammation during pregnancy has been an environmental factor associated with ASD and we have found that loss of one GABRB3 allele in mother and fetus is sufficient to markedly increase placental pathology in response to cytokines produced by a mild maternal innate immune response in mice. In contrast, activating GABA(A) receptors during a maternal immune event attenuates the impact to the fetus. This implicates GABA(A)-related immune alterations and placental vulnerability as a potential gene-environment interaction which is associated with increased risk of ASD and other PDDs. Importantly, the maternal inheritance pattern of 15q11-13 anomalies suggests that GABA(A)-related immune functions may be altered in mother, as well as in the placenta and fetus. The experiments proposed here test whether selective loss of GABARB3 in the mother, placenta or fetus increase the risk of developing autistic features in offspring following a prenatl maternal immune event.
This proposal tests a novel hypothesis that alterations in a gene implicated in autism and autism spectrum disorders may have a unexpected role in making the pregnancy and developing fetus more sensitive to maternal infections for mild illnesses. The studies focus on the GABA(A) receptor, an important receptor expressed by neurons in the brain. The receptor is also expressed by cells of the immune system and we have found that alterations in this receptor that are associated with autism also worsen the impact of maternal illness on the developing fetal brain. Data generated in the proposed experiments may provide information that helps to identify pregnancies at risk as well as informs future studies to develop interventions that protect the at-risk fetus from developmental alterations which might lead to autism.
|Carpentier, Pamela A; Haditsch, Ursula; Braun, Amy E et al. (2013) Stereotypical alterations in cortical patterning are associated with maternal illness-induced placental dysfunction. J Neurosci 33:16874-88|