Autism spectrum disorder (ASD) is increasingly thought to result from low-level deficits in synaptic development and neural circuit formation that cascade into more complex cognitive symptoms. However, the link between synaptic dysfunction and behavior is not well understood. By comparing the effects of abnormal circuit formation and behavioral outcomes across different species, it should be possible to pinpoint the conserved fundamental processes that result in disease. Here we use a novel model for neurodevelopmental disorders in which we expose Xenopus laevis tadpoles to valproic acid (VPA) during a critical time point in brain development at which neurogenesis and neural circuit formation required for sensory processing are occurring. VPA is a commonly prescribed antiepileptic drug with known teratogenic effects. In utero exposure to VPA in humans or rodents results in a higher incidence of ASD or ASD-like behavior later in life. We find that tadpoles exposed to VPA have abnormal sensorimotor and schooling behavior that is accompanied by hyperconnected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity, and decreased neuronal intrinsic excitability. Consistent with these findings, VPA-treated tadpoles also have increased seizure susceptibility and decreased acoustic startle habituation. These findings indicate that the effects of VPA are remarkably conserved across vertebrate species and that changes in neural circuitry resulting from abnormal developmental pruning can cascade into higher-level behavioral deficits.

Objective To review the contribution of the Nurses' Health Studies (NHSs) to identifying epidemiologic factors for multiple skin diseases, including skin cancer, psoriasis, and other inflammatory and autoimmune skin diseases. Methods Narrative review of the publications of the NHSs (1976-2016). Results The cohorts have identified environmental and lifestyle factors of psoriasis, supporting obesity and smoking as psoriasis risk factors; associations of diabetes, myocardial infarction, and Crohn's disease with psoriasis, supporting psoriasis as a systemic disorder; associations of pigmentary traits, UV radiation, and lifestyle factors such as citrus consumption and risk of skin cancer. Genetic studies spanning from candidate gene studies to genome-wide association studies have identified novel genetic loci for skin pigmentation (such as IRF4, SLC24A4, NID1, and EDNRB) and skin cancer (such as TET2 and HERC2-OCA2). Work continues on highly prevalent but less studied skin conditions such as rosacea, acne, and atopic dermatitis. Our results have influenced public health policy on anti-indoor tanning for skin cancer prevention. Conclusion The NHSs have provided invaluable resources on skin disease population science and contributed to the etiologic understanding of multiple skin disorders.

BackgroundFragile X Syndrome is the leading monogenetic cause of autism and most common form of intellectual disability. Previous studies have implicated changes in dendritic spine architecture as the primary result of loss of Fragile X Mental Retardation Protein (FMRP), but recent work has shown that neural proliferation is decreased and cell death is increased with either loss of FMRP or overexpression of FMRP. The purpose of this study was to investigate the effects of loss of FMRP on behavior and cellular activity.MethodsWe knocked down FMRP expression using morpholino oligos in the optic tectum of Xenopus laevis tadpoles and performed a series of behavioral and electrophysiological assays. We investigated visually guided collision avoidance, schooling, and seizure propensity. Using single cell electrophysiology, we assessed intrinsic excitability and synaptic connectivity of tectal neurons.ResultsWe found that FMRP knockdown results in decreased swimming speed, reduced schooling behavior and decreased seizure severity. In single cells, we found increased inhibition relative to excitation in response to sensory input.ConclusionsOur results indicate that the electrophysiological development of single cells in the absence of FMRP is largely unaffected despite the large neural proliferation defect. The changes in behavior are consistent with an increase in inhibition, which could be due to either changes in cell number or altered inhibitory drive, and indicate that FMRP can play a significant role in neural development much earlier than previously thought.