Conformational state-dependent regulation of GABAA receptor diffusion and subsynaptic domains.

The efficacy of GABAergic synapses relies on the number of postsynaptic GABAA receptors (GABAARs), which is regulated by a diffusion capture mechanism. Here, we report that the conformational state of GABAARs influences their membrane dynamics. Indeed, pharmacological and mutational manipulations of receptor favoring active or desensitized states altered GABAAR diffusion leading to the disorganization of GABAAR subsynaptic domains and gephyrin scaffold, as detected by super-resolution microscopy. Active and desensitized receptors were confined to perisynaptic endocytic zones, and some of them were further internalized. We propose that following their activation or desensitization, synaptic receptors rapidly diffuse at the periphery of the synapse where they remain confined until they switch back to a resting state or are internalized. We speculate that this allows a renewal of activatable receptors at the synapse, contributing to maintain the efficacy of the synaptic transmission, in particular on sustained GABA transmission.

Descriptive and Functional Genomics in Acute Myeloid Leukemia (AML): Paving the Road for a Cure.

Over the past decades, genetic advances have allowed a more precise molecular characterization of AML with the identification of novel oncogenes and tumor suppressors as part of a comprehensive AML molecular landscape. Recent advances in genetic sequencing tools also enabled a better understanding of AML leukemogenesis from the preleukemic state to posttherapy relapse. These advances resulted in direct clinical implications with the definition of molecular prognosis classifications, the development of treatment recommendations based on minimal residual disease (MRD) measurement and the discovery of novel targeted therapies, ultimately improving AML patients' overall survival. The more recent development of functional genomic studies, pushed by novel molecular biology technologies (short hairpin RNA (shRNA) and CRISPR-Cas9) and bioinformatics tools design on one hand, along with the engineering of humanized physiologically relevant animal models on the other hand, have opened a new genomics era resulting in a greater knowledge of AML physiopathology. Combining descriptive and functional genomics will undoubtedly open the road for an AML cure within the next decades.