South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; Rehabilitation Center, First Affiliated Hospital of Guangzhou University of CM, Guangzhou, Guangdong, China.
South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
Neurobiol Aging. 2022 Sep;117:165-178. doi: 10.1016/j.neurobiolaging.2022.05.013. Epub 2022 Jun 6.
Neuropsychiatric symptoms, such as anxiety and depression often appear early in patients with Alzheimer's disease (AD), and a comorbid, anxiety-like phenotype is also found in rodents with AD. However, the underlying mechanisms behind these conditions and potential therapeutic targets to treat them remain unclear. In this study, we used 5 familial AD mutations (5xFAD) mice that developed early amyloid β-amyloid deposition and related synaptic loss and memory deficits to identify a potential mechanism behind abnormally high anxiety levels observed in these subjects. We observed anxiety-like behavior in mice that had an excitatory/inhibitory (E/I) imbalance in the ventral hippocampus (vHPC) of 5xFAD mice. Both the number of parvalbumin-positive (PV+) and somatostatin-positive (SST+) cells decreased in the ventral hippocampus of the subject 5xFAD mice, however, no reductions were observed in calretinin-positive cells. We found that selectively inhibiting vHPC pyramidal cells via hM4Di expression normalized anxiety-like behaviors and E/I balance in 5xFAD mice. Finally, we found that the ventral hippocampus SST+ or PV+ neurons were activated through selectively expressed hM3Dq, which ameliorated anxiety-like behaviors and the synaptic E/I imbalance of vCA1 in 5xFAD mice. These results determined that anxiety-like behaviors accompanied by hippocampal synaptic E/I imbalance in 5xFAD mice are due to the loss of SST+ and PV+ interneurons in the vHPC. This provides a better understanding of high anxiety levels observed in patients with early-stage AD.
神经精神症状，如焦虑和抑郁，常出现在阿尔茨海默病（AD）患者的早期，AD 啮齿动物也存在类似焦虑的共病表型。然而，这些疾病背后的潜在机制和潜在的治疗靶点仍不清楚。在这项研究中，我们使用了 5 种家族性 AD 突变（5xFAD）小鼠，这些小鼠出现了早期淀粉样β淀粉样沉积和相关的突触丢失以及记忆缺陷，以确定这些患者中观察到的异常高焦虑水平背后的潜在机制。我们观察到 5xFAD 小鼠腹侧海马（vHPC）兴奋性/抑制性（E/I）失衡的小鼠出现焦虑样行为。5xFAD 小鼠 vHPC 中的 parvalbumin 阳性（PV+）和 somatostatin 阳性（SST+）细胞数量减少，但 calretinin 阳性细胞没有减少。我们发现，通过 hM4Di 表达选择性抑制 vHPC 锥体神经元可使 5xFAD 小鼠的焦虑样行为和 E/I 平衡正常化。最后，我们发现通过选择性表达 hM3Dq 可以激活 vHPC 的 SST+或 PV+神经元，从而改善 5xFAD 小鼠的焦虑样行为和 vCA1 的突触 E/I 失衡。这些结果表明，5xFAD 小鼠的焦虑样行为伴随着海马突触 E/I 失衡，是由于 vHPC 中 SST+和 PV+中间神经元的丧失所致。这为理解早期 AD 患者中观察到的高焦虑水平提供了更好的理解。
