Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
718—Genetic Correlates of Autism
Wednesday, November 13, 2013, 8:00 am - 12:00 noon
718.24: The interaction between α7nAChR and maternal infection in regulating schizophrenia- and autism-like behaviors
Location: Halls B-H
*W.-L. WU, P. H. PATTERSON; Div. of Biol., Caltech, Pasadena, CA
Abstract Body: Microdeletion of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA7, which encodes alpha7 nicotinic acetylcholine receptor (α7nAChR), which is associated with schizophrenia in clinical studies and in rodent models. We are investigating the interaction between α7nAChR and the environmental risk factor, maternal infection. The role of α7nAChR is being examined in two ways. First, we induce maternal immune activation (MIA) by maternal injection of poly(I:C) at mid-gestation, and test the effects of supplementing choline in the diet throughout embryonic and postnatal development until weaning, which would increase cholinergic signaling. Second, we test the behavior of MIA offspring in Chrna7+/- mice. We find that maternal choline supplementation alleviates several schizophrenia- and autistic-like behaviors in MIA male offspring, such as deficits in sensory gating and social interaction, and, increased anxiety and repetitive behaviors. Moreover, compared to wild type mice, results with the Chrna7+/- mice suggest that MIA increases sensory gating deficits. Thus, both perinatal environmental and genetic manipulations of α7nAChR can modulate the MIA-induced autistic/schizophrenia-like phenotype. One hypothesis to explain these results is that α7nAChR regulates the maternal inflammatory response to MIA.
Lay Language Summary: Schizophrenia and autism each affect about 1% of the population in United States. Epidemiologic studies indicate that maternal infection is an important environmental risk factor for both disorders. Maternal infection increases the risk for schizophrenia and autism by activating the mother’s immune system during pregnancy (maternal immune activation; MIA). On the other hand, genetic linkage studies show that CHRNA7, a gene located on human chromosome 15 that codes for the acetylcholine receptor, α7nAChR, is associated with schizophrenia and autism. We are exploring how acetylcholine neurotransmission interacts with the environmental factor to increase the risk for schizophrenia and autism. We find that a safe and straightforward dietary intervention can prevent many of the effects of maternal infection on brain development and behavior. To investigate the role of the neurotransmitter acetylcholine and its receptor, α7nAChR, in maternal infection, we use a mouse model of MIA. To increase the level of α7nAChR-dependent acetylcholine transmission during gestation and weaning, the acetylcholine precursor and α7nAChR agonist, choline, is supplemented in the diet of control and MIA mice. In the converse experiment, MIA is induced in α7nAChR heterozygous pregnant mice, which have only half the normal amount of this receptor. The adult offspring are then tested for some of the core symptoms of schizophrenia and autism. In addition, to investigate whether maternal choline supplementation alters the inflammatory state of the fetal brain during the early stages of infection. MIA offspring developing with a normal diet exhibit deficits in sensorimotor gating, anxiety, sociability, and display more repetitive behavior than control offspring. When α7nAChR-dependent acetylcholine transmission is increased by choline supplementation, many of these abnormalities are ameliorated. Conversely, when α7nAChR level is decreased to lessen acetylcholine transmission in α7nAChR heterozygous MIA offspring, they display a more severe sensorimotor gating deficit and anxiety. That is, when acetylcholine neurotransmission is diminished, some symptoms are worse, and when acetylcholine transmission is increased, some symptoms are lessoned. Analysis of the fetal brains during MIA shows that the pro-inflammatory cytokine, IL-6, is higher than in control fetal brains. When choline is supplemented to the diet of the MIA mothers, IL-6 levels are lowered in the fetal brain. Neuropathology studies show that in the MIA fetus, neurons expressing the α7nAChR do not migrate properly during development. These findings raise the questions of whether the abnormal behaviors in the offspring are caused by this abnormal neuronal migration, and whether the inflammatory cytokine IL-6 influences this migration defect. The results with this mouse model provide support for the efficacy of choline supplementation to reduce the possibility of brain inflammation and the risk of schizophrenia and autism following maternal infection. It is noteworthy that choline supplementation is safe, inexpensive and easy to administer.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit