The dentate gyrus (DG) controls information flow into the hippocampus and is critical for learning, memory, pattern separation, and spatial coding, while DG dysfunction is associated with neuropsychiatric disorders. Despite its importance, the molecular mechanisms regulating DG neural circuit assembly and function remain unclear. Here, we identify the Rac-GEF Tiam1 as an important regulator of DG development and associated memory processes. In the hippocampus, Tiam1 is predominantly expressed in the DG throughout life. Global deletion of Tiam1 in male mice results in DG granule cells with simplified dendritic arbors, reduced dendritic spine density, and diminished excitatory synaptic transmission. Notably, DG granule cell dendrites and synapses develop normally in Tiam1 KO mice, resembling WT mice at postnatal day 21 (P21), but fail to stabilize, leading to dendrite and synapse loss by P42. These results indicate that Tiam1 promotes DG granule cell dendrite and synapse stabilization late in development. Tiam1 loss also increases the survival, but not the production, of adult-born DG granule cells, possibly because of greater circuit integration as a result of decreased competition with mature granule cells for synaptic inputs. Strikingly, both male and female mice lacking Tiam1 exhibit enhanced contextual fear memory and context discrimination. Together, these results suggest that Tiam1 is a key regulator of DG granule cell stabilization and function within hippocampal circuits. Moreover, based on the enhanced memory phenotype of Tiam1 KO mice, Tiam1 may be a potential target for the treatment of disorders involving memory impairments.

SIGNIFICANCE STATEMENT The dentate gyrus (DG) is important for learning, memory, pattern separation, and spatial navigation, and its dysfunction is associated with neuropsychiatric disorders. However, the molecular mechanisms controlling DG formation and function remain elusive. By characterizing mice lacking the Rac-GEF Tiam1, we demonstrate that Tiam1 promotes the stabilization of DG granule cell dendritic arbors, spines, and synapses, whereas it restricts the survival of adult-born DG granule cells, which compete with mature granule cells for synaptic integration. Notably, mice lacking Tiam1 also exhibit enhanced contextual fear memory and context discrimination. These findings establish Tiam1 as an essential regulator of DG granule cell development, and identify it as a possible therapeutic target for memory enhancement.

齿状回 (DG) 控制进入海马体的信息流，对于学习、记忆、模式分离和空间编码至关重要，而 DG 功能障碍与神经精神疾病有关。尽管它很重要，但调节 DG 神经回路组装和功能的分子机制仍不清楚。在这里，我们将 Rac-GEF Tiam1 确定为 DG 发育和相关记忆过程的重要调节因子。在海马体中，Tiam1 在整个生命过程中主要在 DG 中表达。雄性小鼠中Tiam1的整体缺失会导致 DG 颗粒细胞的树突乔木简化、树突棘密度降低以及兴奋性突触传递减弱。值得注意的是，DG 颗粒细胞树突和突触在Tiam1 KO 小鼠中正常发育，类似于出生后第 21 天（P21）的 WT 小鼠，但未能稳定，导致 P42 导致树突和突触损失。这些结果表明 Tiam1 促进发育后期 DG 颗粒细胞树突和突触的稳定。 Tiam1 缺失也会增加成年 DG 颗粒细胞的存活率，但不会增加其产量，这可能是由于与成熟颗粒细胞对突触输入的竞争减少而导致的更大的电路整合。引人注目的是，缺乏 Tiam1 的雄性和雌性小鼠都表现出增强的情境恐惧记忆和情境辨别能力。总之，这些结果表明 Tiam1 是海马回路内 DG 颗粒细胞稳定和功能的关键调节因子。此外，基于Tiam1 KO 小鼠的记忆增强表型，Tiam1 可能是治疗记忆障碍疾病的潜在靶点。

意义陈述齿状回（DG）对于学习、记忆、模式分离和空间导航很重要，其功能障碍与神经精神疾病有关。然而，控制 DG 形成和功能的分子机制仍然难以捉摸。通过表征缺乏 Rac-GEF Tiam1 的小鼠，我们证明 Tiam1 促进 DG 颗粒细胞树突轴、棘和突触的稳定，同时限制成年 DG 颗粒细胞的存活，这些细胞与成熟颗粒细胞竞争突触。一体化。值得注意的是，缺乏 Tiam1 的小鼠还表现出增强的情境恐惧记忆和情境辨别能力。这些发现证实 Tiam1 是 DG 颗粒细胞发育的重要调节因子，并将其确定为增强记忆的可能治疗靶点。