Nagarajan Rajasekar, Lyu Jinrui, Kambali Maltesh, Wang Muxiao, Courtney Connor D, Christian-Hinman Catherine A, Rudolph Uwe
Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Mol Neurobiol. 2024 Feb;61(2):567-580. doi: 10.1007/s12035-023-03586-3. Epub 2023 Aug 29.
Aging is often associated with a decline in cognitive function. A reduction in the number of somatostatin-positive (SOM) interneurons in the dentate gyrus (DG) has been described in cognitively impaired but not in unimpaired aged rodents. However, it remains unclear whether the reduction in SOM + interneurons in the DG hilus is causal for age-related cognitive dysfunction. We hypothesized that hilar SOM interneurons play an essential role in maintaining cognitive function and that a reduction in the number of hilar SOM + interneurons might be sufficient to induce cognitive dysfunction. Hilar SOM interneurons were ablated by expressing a diphtheria toxin transgene specifically in these interneurons, which resulted in a reduction in the number of SOM /GAD-67 neurons and dendritic spine density in the DG. C-fos and Iba-1 immunostainings were increased in DG and CA3, but not CA1, and BDNF protein expression in the hippocampus was decreased. Behavioral testing showed a reduced recognition index in the novel object recognition test, decreased alternations in the Y maze test, and longer latencies and path lengths in the learning and reversal learning phases of the Morris water maze. Our results show that partial genetic ablation of SOM hilar interneurons is sufficient to increase activity in DG and CA3, as has been described to occur with aging and to induce an impairment of learning and memory functions. Thus, partial ablation of hilar SOM + interneurons may be a significant contributing factor to age-related cognitive dysfunction. These mice may also be useful as a cellularly defined model of hippocampal aging.
衰老通常与认知功能下降有关。在认知受损的老年啮齿动物中，已观察到齿状回（DG）中生长抑素阳性（SOM）中间神经元数量减少，但在未受损的老年啮齿动物中未观察到这种情况。然而，DG门区SOM⁺中间神经元数量的减少是否是与年龄相关的认知功能障碍的原因仍不清楚。我们假设门区SOM中间神经元在维持认知功能中起重要作用，门区SOM⁺中间神经元数量的减少可能足以诱发认知功能障碍。通过在这些中间神经元中特异性表达白喉毒素转基因来消融门区SOM中间神经元，这导致DG中SOM⁺/GAD-67神经元数量和树突棘密度降低。DG和CA3区（而非CA1区）的C-fos和Iba-1免疫染色增加，海马体中的BDNF蛋白表达降低。行为测试显示，在新物体识别测试中识别指数降低，在Y迷宫测试中交替次数减少，在莫里斯水迷宫的学习和逆向学习阶段潜伏期和路径长度延长。我们的结果表明，SOM门区中间神经元的部分基因消融足以增加DG和CA3区的活性，这与衰老时发生的情况一致，并导致学习和记忆功能受损。因此，门区SOM⁺中间神经元的部分消融可能是与年龄相关的认知功能障碍的一个重要促成因素。这些小鼠也可能作为海马衰老的细胞定义模型有用。
