On Sep.5, 2019, Yi Zhong's group published ’Genetic dissection of active forgetting in labile and consolidated memories in Drosophila’ in PNAS.
As a critical component of a healthy memory management system, forgetting has received increasing attention. Studies across multiple species support important roles of actin remodeling in forgetting. However, the underlying molecular mechanisms remain unclear. In Drosophila, Rac1 and Cdc42, 2 Rho GTPases that act as signaling hubs to coordinate actin remodeling, were reported to mediate the forgetting of labile and consolidated memories, respectively. Here, we showed that Rac1 and Cdc42 exert their effects on forgetting by acting through 2 different actin polymerization pathways, Rac1/SCAR/Dia and Cdc42/WASp/Arp2/3 complexes. These findings fill in the molecular landscape that link forgetting to actin remodeling at the cellular level and shed light on drug development that aims to tune forgetting to treat memory-related diseases.
Different memory components are forgotten through distinct molecular mechanisms. In Drosophila, the activation of 2 Rho GTPases (Rac1 and Cdc42), respectively, underlies the forgetting of an early labile memory (anesthesia-sensitive memory, ASM) and a form of consolidated memory (anesthesia-resistant memory, ARM). Here, we dissected the molecular mechanisms that tie Rac1 and Cdc42 to the different types of memory forgetting. We found that 2 WASP family proteins, SCAR/WAVE and WASp, act downstream of Rac1 and Cdc42 separately to regulate ASM and ARM forgetting in mushroom body neurons. Arp2/3 complex, which organizes branched actin polymerization, is a canonical downstream effector of WASP family proteins. However, we found that Arp2/3 complex is required in Cdc42/WASp-mediated ARM forgetting but not in Rac1/SCAR-mediated ASM forgetting. Instead, we identified that Rac1/SCAR may function with formin Diaphanous (Dia), a nucleator that facilitates linear actin polymerization, in ASM forgetting. The present study, complementing the previously identified Rac1/cofilin pathway that regulates actin depolymerization, suggests that Rho GTPases regulate forgetting by recruiting both actin polymerization and depolymerization pathways. Moreover, Rac1 and Cdc42 may regulate different types of memory forgetting by tapping into different actin polymerization mechanisms.