Memory loss is often seen as a cognitive failure or a pathological symptom. However, optimal cognitive performance requires the brain to actively suppress old, unused, or unwanted memories to make room for new ones. In flies, this form of active forgetting is mediated in part by the guanosine triphosphatase Rac1 and the dopamine receptor Damb in mushroom body neurons (MBn), which are innervated by dopaminergic neurons. Cervantes-Sandoval et al. found that active forgetting in flies is promoted by a dopamine-induced “forgetting signalosome” involving Rac1 and the protein Scribble. A Drosophila screen for genes that when inhibited by RNA-interference enhanced memory in an olfactory conditioning test identified scrb, encoding Scribble, a scaffolding protein that functions in epithelial cell polarity and neuronal synaptic structure. Additional tests involving either electric shock or interference-based tests that stimulate forgetting and rewriting of olfactory memories showed that memory enhancement in Scribble-deficient flies was not because of improved acquisition or consolidation but rather was because of decreased forgetting. Cell type–specific knockdown revealed that this impaired forgetting occurred only when Scribble was knocked down in either dopaminergic neurons or the subset of the MBn in which Rac1 and Damb were previously implicated in active memory loss. Various experiments revealed that Scribble physically interacted with Rac1, the Rac-activated kinase Pak3, and the cytoskeleton regulator cofilin to form a “forgetting signalosome” that was activated by dopaminergic input to the MBn. The findings place Scribble in a scaffolding role that mediates dopaminergic-induced forgetting.
I. Cervantes-Sandoval, M. Chakraborty, C. MacMullen, R. L. Davis, Scribble scaffolds a signalosome for active forgetting. Neuron 90, 1230–1242 (2016). [PubMed]