Synaptic and transcriptionally downregulated genes are associated with cortical thickness differences in autism.

Differences in cortical morphology-in particular, cortical volume, thickness and surface area-have been reported in individuals with autism. However, it is unclear what aspects of genetic and transcriptomic variation are associated with these differences. Here we investigate the genetic correlates of global cortical thickness differences (ΔCT) in children with autism. We used Partial Least Squares Regression (PLSR) on structural MRI data from 548 children (166 with autism, 295 neurotypical children and 87 children with ADHD) and cortical gene expression data from the Allen Institute for Brain Science to identify genetic correlates of ΔCT in autism. We identify that these genes are enriched for synaptic transmission pathways and explain significant variation in ΔCT. These genes are also significantly enriched for genes dysregulated in the autism post-mortem cortex (Odd Ratio (OR) = 1.11, Pcorrected  10-14), driven entirely by downregulated genes (OR = 1.87, Pcorrected  10-15). We validated the enrichment for downregulated genes in two independent data sets: Validation 1 (OR = 1.44, Pcorrected = 0.004) and Validation 2 (OR = 1.30; Pcorrected = 0.001). We conclude that transcriptionally downregulated genes implicated in autism are robustly associated with global changes in cortical thickness variability in children with autism

Membrane Microdomains and cAMP Compartmentation in Cardiac Myocytes

Signaling through the diffusible second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) is critical to the regulation of cardiac function. Several different G-protein-coupled receptors, including β-adrenergic receptors, muscarinic receptors, and E-type prostaglandin receptors, elicit distinct responses using this ubiquitous second messenger. One critical paradigm that has emerged to explain this behavior is that cAMP signaling is compartmentalized. Spatially confining specific receptors and their downstream effector proteins to form subcellular signaling complexes has been proposed to allow for the high efficiency and fidelity in producing specific functional responses. In cardiac myocytes, lipid rafts created by cholesterol- and sphingolipid-rich membrane microdomains have been demonstrated to act as one means of sorting appropriate receptors and corresponding effectors to relevant subcellular locations. Caveolae, which represent a specific subset of lipid rafts, can dynamically attract or exclude specific signaling proteins through a variety of mechanisms to create highly localized and self-sufficient multi-molecular signaling complexes. Furthermore, disruption of this organization in disease states such as heart failure has been found to alter cAMP responses. In this review, we summarize the current understanding of the role of membrane domains in cAMP signaling in cardiac myocytes. We also highlight the insights gained from previous studies to offer new avenues of research in this expanding field of study.https://digitalcommons.chapman.edu/pharmacy_books/1021/thumbnail.jp