The remedy of memory deficits has been inadequate, as all potential candidates studied thus far have shown limited to no effects and a search for an effective strategy is ongoing. Here, we show that an expression of RGS14414 in rat perirhinal cortex (PRh) produced long-lasting object recognition memory (ORM) enhancement and that this effect was mediated through the upregulation of 14-3-3ζ, which caused a boost in BDNF protein levels and increase in pyramidal neuron dendritic arborization and dendritic spine number. A knockdown of the 14-3-3ζ gene in rat or the deletion of the BDNF gene in mice caused complete loss in ORM enhancement and increase in BDNF protein levels and neuronal plasticity, indicating that 14-3-3ζ-BDNF pathway-mediated structural plasticity is an essential step in RGS14414-induced memory enhancement. We further observed that RGS14414 treatment was able to prevent deficits in recognition, spatial, and temporal memory, which are types of memory that are particularly affected in patients with memory dysfunctions, in rodent models of aging and Alzheimer’s disease. These results suggest that 14-3-3ζ-BDNF pathway might play an important role in the maintenance of the synaptic structures in PRh that support memory functions and that RGS14414-mediated activation of this pathway could serve as a remedy to treat memory deficits.

中文翻译：

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RGS14414-介导的啮齿动物 Perirhinal Cortex 中 14-3-3ζ 的激活诱导树突树枝状化、脊柱数量增加、持久记忆增强和预防记忆缺陷

记忆缺陷的补救措施一直不够，因为迄今为止研究的所有潜在候选人都显示出有限的效果，并且正在寻找有效的策略。在这里，我们表明 RGS14414 在大鼠鼻周皮层 (PRh) 中的表达产生了持久的物体识别记忆 (ORM) 增强，并且这种效应是通过 14-3-3ζ 的上调介导的，这导致了 BDNF 蛋白的增加水平和锥体神经元树突树枝状化和树突棘数量的增加。大鼠 14-3-3ζ 基因敲低或小鼠 BDNF 基因缺失导致 ORM 增强完全丧失，BDNF 蛋白水平和神经元可塑性增加，表明 14-3-3ζ-BDNF 通路介导的结构可塑性是 RGS14414 诱导的记忆增强的重要步骤。我们进一步观察到，RGS14414 治疗能够预防在衰老和阿尔茨海默病啮齿动物模型中识别、空间和时间记忆的缺陷，这些记忆类型在记忆功能障碍患者中尤其受到影响。这些结果表明，14-3-3ζ-BDNF 通路可能在维持 PRh 中支持记忆功能的突触结构中发挥重要作用，并且 RGS14414 介导的该通路激活可作为治疗记忆缺陷的药物。