Lyu Jinrui, Nagarajan Rajasekar, Kambali Maltesh, Wang Muxiao, Rudolph Uwe
Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802-6178, USA.
Neuroscience Program, College of Liberal Arts and Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61802-6178, USA.
PNAS Nexus. 2023 Apr 13;2(5):pgad134. doi: 10.1093/pnasnexus/pgad134. eCollection 2023 May.
The cellular basis of age-related impairments of hippocampal function is not fully understood. In order to evaluate the role of somatostatin-positive (Sst) interneurons in the dentate gyrus (DG) hilus in this process, we chemogenetically inhibited Sst interneurons in the DG hilus. Chronic chemogenetic inhibition (CCI) of these neurons resulted in increased c-Fos staining in the DG hilus, a decrease in the percentage of GAD67- and of Sst-expressing interneurons in the DG, and increased microglial activation in DG, CA3, and CA1. Total dendritic length and spine density were reduced in DG and CA1, suggesting reduced dendritic complexity. Behaviorally, the recognition index in an object recognition task and the percentage of spontaneous alternations in the Y-maze were decreased, while in both initial and reversal learning in the Morris water maze, the latencies to find the hidden platform were increased, suggesting cognitive dysfunction. Our findings establish a causal role for a reduced function of Sst interneurons in the DG hilus for cognitive decline and suggest that this reduced function may contribute to age-related impairments of learning and memory. Furthermore, our CCI mice may represent a cellularly defined model of hippocampal aging.
海马体功能与年龄相关损伤的细胞基础尚未完全明确。为了评估齿状回（DG）门区生长抑素阳性（Sst）中间神经元在此过程中的作用，我们采用化学遗传学方法抑制了DG门区的Sst中间神经元。对这些神经元进行慢性化学遗传学抑制（CCI）导致DG门区c-Fos染色增加，DG中表达GAD67和Sst的中间神经元百分比降低，以及DG、CA3和CA1区小胶质细胞活化增加。DG和CA1区的总树突长度和棘密度降低，提示树突复杂性降低。行为学上，物体识别任务中的识别指数和Y迷宫中的自发交替百分比降低，而在Morris水迷宫的初始学习和逆向学习中，找到隐藏平台的潜伏期均增加，提示存在认知功能障碍。我们的研究结果确定了DG门区Sst中间神经元功能减退在认知衰退中的因果作用，并表明这种功能减退可能导致与年龄相关的学习和记忆损伤。此外，我们的CCI小鼠可能代表一种细胞层面定义的海马体衰老模型。
