ABSTRACT
Genetic mutations identified in genome-wide association studies can only explain a small percentage of the cases of complex, highly heritable human conditions, including neurological and neurodevelopmental disorders. This suggests that intergenerational epigenetic effects, possibly triggered by environmental circumstances, may contribute to their etiology. We previously described altered DNA methylation signatures in the sperm of mice that experienced developmental overexposure to thyroid hormones as a result of a genetic defect in hormone clearance (DIO3 deficiency). Here we studied fetal brain gene expression and adult social behavior in genetically normal F2 generation descendants of overexposed mice. The brain of F2 generation E13.5 fetuses exhibited abnormal expression of genes associated with autism in humans, including Auts2, Disc1, Ldlr, Per2, Shank3, Oxtr, Igf1, Foxg1, Cd38, Grid2, Nrxn3, and Reln. These abnormal gene expression profiles differed depending on the sex of the exposed ancestor. In the three-chamber social box test, adult F2 generation males manifested significantly decreased interest in social interaction and social novelty, as revealed by decrease total time, distance traveled and time immobile in the area of interaction with novel strangers. F1 generation mice, compared to appropriate controls also exhibited altered profiles in fetal brain gene expression, although these profiles were substantially different to those in the F2 generation. Likewise adult F1 generation mice showed some abnormalities in social behavior that were sexually dimorphic and milder than those in F2 generation mice. Our results indicate that developmental overexposure to thyroid hormone causes intergenerational epigenetic effects impacting social behavior and the expression of autism-related genes during early brain development. Our results open the possibility that altered thyroid hormone states, by eliciting changes in the epigenetic information of the germ line, contribute to the susceptibility and the missing-but heriTables-etiology of complex neurodevelopmental conditions characterized by social deficits, including autism and schizophrenia.
ABSTRACT
Phosphoinositides are members of a family of minor phospholipids that make up about 1% of all lipids in most cell types. Despite their low abundance they have been found to be essential regulators of neuronal activities such as action potential firing, release and re-uptake of neurotransmitters, and interaction of cytoskeletal proteins with the plasma membrane. Activation of several different neurotransmitter receptors can deplete phosphoinositide levels by more than 90% in seconds, thereby profoundly altering neuronal behavior; however, despite the physiological importance of this mechanism we still lack a profound quantitative understanding of the connection between phosphoinositide metabolism and neuronal activity. Here, we present a model that describes phosphoinositide metabolism and phosphoinositide-dependent action potential firing in sympathetic neurons. The model allows for a simulation of activation of muscarinic acetylcholine receptors and its effects on phosphoinositide levels and their regulation of action potential firing in these neurons. In this paper, we describe the characteristics of the model, its calibration to experimental data, and use the model to analyze how alterations of surface density of muscarinic acetylcholine receptors or altered activity levels of a key enzyme of phosphoinositide metabolism influence action potential firing of sympathetic neurons. In conclusion, the model provides a comprehensive framework describing the connection between muscarinic acetylcholine signaling, phosphoinositide metabolism, and action potential firing in sympathetic neurons which can be used to study the role of these signaling systems in health and disease.