Ras-related C3 botulinum toxin substrate 1 (Rac1) is a small GTPase that regulates actin cytoskeleton dynamics and synaptic plasticity. Rac1 has been implicated in active forgetting, but whether it also constrains the consolidation of new memories remains unclear. Here we show that systemic administration of the Rac1 inhibitor 1A-116 after training in the novel object recognition task markedly extends memory persistence in rats. A single post-training injection of 1A-116 enhanced recognition memory for at least 28 days without altering locomotor- or anxiety-related behaviors. When given after a brief, sub-threshold training session that normally supports only short-term memory, 1A-116 enabled long-term retention that required hippocampal protein synthesis. This promnesic effect was time-dependent, independent of sex, and consistent with Rac1 acting as a negative regulator of memory consolidation rather than merely promoting forgetting. These findings indicate that Rac1 activity after learning limits the consolidation process itself, functioning as a molecular brake on recognition memory stabilization, and suggest that its inhibition may represent a therapeutic avenue to enhance cognitive durability in both healthy and pathological conditions. Significance Statement Memory persistence is shaped by both consolidation and active forgetting, yet the molecular constraints that determine how long a memory lasts remain partially understood. We demonstrate that Rac1, a small GTPase involved in actin remodeling, serves as a negative regulator of hippocampal-dependent recognition memory consolidation. Pharmacological inhibition of Rac1 after learning not only enhances retention but also enables long-term memory formation from sub-threshold training through a hippocampal protein synthesis-dependent mechanism. These findings identify Rac1 activity as a molecular brake on memory stabilization and suggest that its inhibition may enhance cognitive persistence and resilience against age- or disease-related decline.
Borges et al. (Tue,) studied this question.