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* Abbreviations: HMD: : hyaline membrane disease NIH: : National Institutes of Health UCLA: : University of California, Los Angeles Mary Ellen Avery, MD. Photograph kindly provided by Rosalind S. Brown, MD. How do the lungs of newborns support their first breaths, and why do some infants develop respiratory distress? This crucial research question emerged in the 1950s and was investigated by numerous physicians and scientists, including the American pediatrician Mary Ellen Avery, who devoted her career to the regulation of infant respiration. In a 1964 lecture, Avery drew a distinction between the intrauterine and extrauterine environments stating that “It is clearly at birth that regular rhythmic respiration begins. Something is turned on, something must be different just after birth from the way it was before, and this something must be essential to the regulation of respiration.”(1) Although Avery was a physician by training and not a scientist, research played a significant role in her career and led to her prominence as one of the investigational leaders of respiratory distress syndrome, which was known as hyaline membrane disease (HMD) during the time of Avery’s research. Avery focused on the role of surfactant, specifically its deficiency in HMD, challenging the accepted view at the time that HMD was caused by an obstruction in the lungs due to the aspiration of hyaline membranes. (2)(3)(4) Avery’s act of shifting the understanding of HMD from an obstructive disease to one of a biochemical deficiency was all the more striking given her role as a pediatrician and not a formally trained laboratory scientist. Biographers have estimated that her findings on HMD and their subsequent translation to treatment in the form of surfactant replacement have saved the lives of more than 800,000 infants. (2) The discovery of surfactant deficiency as the cause of HMD in 1959 not only challenged the accepted understanding of the disease at the time, but …

Accumulating evidence suggests that cerebellar dysfunction early in life is associated with autism spectrum disorder (ASD), but the molecular mechanisms underlying the cerebellar deficits at the cellular level are unclear. Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that often presents with ASD. Here, we developed a cerebellar Purkinje cell (PC) model of TSC with patient-derived human induced pluripotent stem cells (hiPSCs) to characterize the molecular mechanisms underlying cerebellar abnormalities in ASD and TSC. Our results show that hiPSC-derived PCs from patients with pathogenic TSC2 mutations displayed mTORC1 pathway hyperactivation, defects in neuronal differentiation and RNA regulation, hypoexcitability and reduced synaptic activity when compared with those derived from controls. Our gene expression analyses revealed downregulation of several components of fragile X mental retardation protein (FMRP) targets in TSC2-deficient hiPSC-PCs. We detected decreased expression of FMRP, glutamate receptor δ2 (GRID2), and pre- and post-synaptic markers such as synaptophysin and PSD95 in the TSC2-deficient hiPSC-PCs. The mTOR inhibitor rapamycin rescued the deficits in differentiation, synaptic dysfunction, and hypoexcitability of TSC2 mutant hiPSC-PCs in vitro. Our findings suggest that these gene expression changes and cellular abnormalities contribute to aberrant PC function during development in TSC affected individuals.