Detalle de: Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome

Significance Neurons coregulate their number of synapses and the probability of neurotransmitter release per synapse in an antagonistic manner. The binding of neuronal calcium sensor 1 (NCS-1) to the guanine exchange factor protein Ric8a coregulates these neuronal features. This study identified a small molecule, the phenothiazine FD44, that binds the interaction surface between NCS-1 and Ric8a, preventing the formation of the complex. Tested on a Drosophila model of the fragile X syndrome, where the number of synapses is in excess, FD44 proves effective to reduce synapse number to normal levels and restore normal learning performance. Our structure–function study shows the specificity of this compound and the drugability of the NCS-1/Ric8a interface for the treatment of fragile X and possibly, other synaptopathies.