Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Hippocampus. 2022 Nov;32(11-12):797-807. doi: 10.1002/hipo.23469. Epub 2022 Sep 5.
Understanding the role of dentate gyrus (DG) mossy cells (MCs) in learning and memory has rapidly evolved due to increasingly precise methods for targeting MCs and for in vivo recording and activity manipulation in rodents. These studies have shown MCs are highly active in vivo, strongly remap to contextual manipulation, and that their inhibition or hyperactivation impairs pattern separation and location or context discrimination. Less well understood is how MC activity is modulated by neurohormonal mechanisms, which might differentially control the participation of MCs in cognitive functions during discrete states, such as hunger or satiety. In this study, we demonstrate that glucagon-like peptide-1 (GLP-1), a neuropeptide produced in the gut and the brain that regulates food consumption and hippocampal-dependent mnemonic function, might regulate MC function through expression of its receptor, GLP-1R. RNA-seq demonstrated that most, though not all, Glp1r in hippocampal principal neurons is expressed in MCs, and in situ hybridization revealed strong expression of Glp1r in hilar neurons. Glp1r-ires-Cre mice crossed with Ai14D reporter mice followed by co-labeling for the MC marker GluR2/3 revealed that almost all MCs in the ventral DG expressed Glp1r and that almost all Glp1r-expressing hilar neurons were MCs. However, only ~60% of dorsal DG MCs expressed Glp1r, and Glp1r was also expressed in small hilar neurons that were not MCs. Consistent with this expression pattern, peripheral administration of the GLP-1R agonist exendin-4 (5 μg/kg) increased cFos expression in ventral but not dorsal DG hilar neurons. Finally, whole-cell patch-clamp recordings from ventral MCs showed that bath application of exendin-4 (200 nM) depolarized MCs and increased action potential firing. Taken together, this study adds to known MC activity modulators a neurohormonal mechanism that may preferentially affect ventral DG physiology and may potentially be targetable by several GLP-1R pharmacotherapies already in clinical use.
理解齿状回（DG）苔藓细胞（MCs）在学习和记忆中的作用，由于针对 MCs 的方法越来越精确，以及在啮齿动物中进行体内记录和活动操作，这一研究迅速发展起来。这些研究表明，MCs 在体内非常活跃，强烈地重新映射到上下文处理，并且它们的抑制或过度激活会损害模式分离和位置或上下文的辨别。不太清楚的是，神经激素机制如何调节 MC 的活动，这可能会在不同的状态下（如饥饿或饱腹），以不同的方式控制 MC 参与认知功能。在这项研究中，我们证明了胰高血糖素样肽-1（GLP-1），一种在肠道和大脑中产生的神经肽，它调节食物的摄入和海马依赖的记忆功能，可能通过其受体 GLP-1R 来调节 MC 的功能。RNA-seq 表明，海马主要神经元中的大多数（尽管不是全部）Glp1r 都在 MCs 中表达，原位杂交显示，在颗粒细胞层神经元中强烈表达 Glp1r。Glp1r-ires-Cre 小鼠与 Ai14D 报告小鼠杂交，然后用 MC 标记物 GluR2/3 进行共标记，结果表明，腹侧 DG 中的几乎所有 MC 都表达 Glp1r，并且几乎所有表达 Glp1r 的颗粒细胞层神经元都是 MC。然而，只有~60%的背侧 DG MC 表达 Glp1r，Glp1r 也表达在不是 MC 的小颗粒细胞层神经元中。与这种表达模式一致，外周给予 GLP-1R 激动剂 exendin-4（5μg/kg）增加了腹侧但不是背侧 DG 颗粒细胞层神经元的 cFos 表达。最后，对腹侧 MC 进行全细胞膜片钳记录显示，exendin-4（200 nM）在浴液中的应用使 MC 去极化并增加动作电位放电。总的来说，这项研究增加了已知的 MC 活动调节剂，增加了一种神经激素机制，这种机制可能优先影响 DG 生理学，并且可能成为几种 GLP-1R 治疗药物的靶点，这些药物已经在临床使用。
