Fragile X syndrome (FXS), caused by loss of FMR1 gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 protein (FMRP) translational regulator mediates activity-dependent control of synapses. In addition to the metabotropic glutamate receptor (mGluR) hyperexcitation FXS theory, the GABA theory postulates that hypoinhibition is causative for disease state symptoms. Here, we use the Drosophila FXS model to assay central brain GABAergic circuitry, especially within the Mushroom Body (MB) learning center. All 3 GABAA receptor (GABAAR) subunits are reportedly downregulated in dfmr1 null brains. We demonstrate parallel downregulation of glutamic acid decarboxylase (GAD), the rate-limiting GABA synthesis enzyme, although GABAergic cell numbers appear unaffected. Mosaic analysis with a repressible cell marker (MARCM) single-cell clonal studies show that dfmr1 null GABAergic neurons innervating the MB calyx display altered architectural development, with early underdevelopment followed by later overelaboration. In addition, a new class of extra-calyx terminating GABAergic neurons is shown to include MB intrinsic α/β Kenyon Cells (KCs), revealing a novel level of MB inhibitory regulation. Functionally, dfmr1 null GABAergic neurons exhibit elevated calcium signaling and altered kinetics in response to acute depolarization. To test the role of these GABAergic changes, we attempted to pharmacologically restore GABAergic signaling and assay effects on the compromised MB-dependent olfactory learning in dfmr1 mutants, but found no improvement. Our results show that GABAergic circuit structure and function are impaired in the FXS disease state, but that correction of hypoinhibition alone is not sufficient to rescue a behavioral learning impairment.

Low mobility during hospitalization poses risks of functional decline and other poor outcomes for older adults. Given the pervasiveness of this problem, low mobility during hospitalization was first described as ‘dangerous’ in 1947 and later described as an epidemic. Hospitals have made considerable progress over the last half-century and the last two decades in particular, however, the COVID-19 pandemic presents serious new challenges that threaten to undermine recent efforts and progress towards a culture of mobility. In this special article, we address the question of how to confront an epidemic of immobility within a pandemic. We identify 4 specific problems for creating and advancing a culture of mobility posed by COVID-19: social distancing and policies restricting patient movement, personnel constraints, PPE shortages, and increased patient hesitancy to ambulate. We also propose 4 specific solutions to address these problems. These approaches will help support a culture of healthy mobility during and after hospitalization and help patients to keep moving during the pandemic and beyond.

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Bold values are statistically significant. CRC indicates closed reduction and casting; ESIN, elastic stable intramedullary nail; N, frequency; N%, divided by total in each group (ESIN = 72; CRC = 69); OR, operating room.