Roles of Rac1-Dependent Intrinsic Forgetting in Memory-Related Brain Disorders: Demon or Angel

Abstract

Animals are required to handle daily massive amounts of information in an ever-changing environment, and the resulting memories and experiences determine their survival and development, which is critical for adaptive evolution. However, intrinsic forgetting, which actively deletes irrelevant information, is equally important for memory acquisition and consolidation. Recently, it has been shown that Rac1 activity plays a key role in intrinsic forgetting, maintaining the balance of the brain's memory management system in a controlled manner. In addition, dysfunctions of Rac1-dependent intrinsic forgetting may contribute to memory deficits in neurological and neurodegenerative diseases. Here, these new findings will provide insights into the neurobiology of memory and forgetting, pathological mechanisms and potential therapies for brain disorders that alter intrinsic forgetting mechanisms.

Keywords: Alzheimer’s disease; Rac1; autistic symptoms; intrinsic forgetting.

Figure 1

Potential mechanisms underlying memory homeostasis. Once a new memory is formed, it is mediated by both consolidation and forgetting. Consolidation allows valuable or strong memories to remain, while forgetting eliminates irrelevant (including previously well consolidated) or weak memories. Forgetting and consolidation signals continue to compete and are modulated by internal or external factors, ultimately determining the fate of the newly acquired memory.

Figure 2

Schematic representations of the tertiary structure of human Rac1 in the low-affinity state. Rac1 consists of one central β-sheet with six strands, six α-helices, and two short 3₁₀ helices. The structure is obtained from the RCSB Protein Data Bank (RCSB PDB) (Toyama et al., 2019 [115]). Abbreviations: DH domain, Dbl-homology domain.

Figure 3

Schematic diagram of major mechanisms of Rac1-dependent intrinsic active forgetting in Drosophila. Abbreviations: Rac1, Ras-related C3 botulinum toxin substrate 1; GTP, guanosine triphosphate; GDP, guanosine diphosphate; GEFs, guanosine nucleotide exchange factors; GAPs, GTPases activating proteins; PAK, p21-activated kinase; LIMK, Lin11, Isl-1 and Mec-3 kinase; DAMB receptor, the dopamine receptor in the mushroom body; P, phosphorylation.