Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
Division of Molecular Psychiatry, Department of Psychiatry and Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
Int J Neuropsychopharmacol. 2023 Apr 17;26(4):294-306. doi: 10.1093/ijnp/pyad008.
Electroconvulsive seizure therapy is often used in both treatment-resistant and geriatric depression. However, preclinical studies identifying targets of chronic electroconvulsive seizure (ECS) are predominantly focused on animal models in young adulthood. Given that putative transcriptional, neurogenic, and neuroplastic mechanisms implicated in the behavioral effects of chronic ECS themselves exhibit age-dependent modulation, it remains unknown whether the molecular and cellular targets of chronic ECS vary with age.
We subjected young adult (2-3 months) and middle-aged (12-13 months), male Sprague Dawley rats to sham or chronic ECS and assessed for despair-like behavior, hippocampal gene expression, hippocampal neurogenesis, and neuroplastic changes in the extracellular matrix, reelin, and perineuronal net numbers.
Chronic ECS reduced despair-like behavior at both ages, accompanied by overlapping and unique changes in activity-dependent and trophic factor gene expression. Although chronic ECS had a similar impact on quiescent neural progenitor numbers at both ages, the eventual increase in hippocampal progenitor proliferation was substantially higher in young adulthood. We noted a decline in reelin⁺ cell numbers following chronic ECS only in young adulthood. In contrast, an age-invariant, robust dissolution of perineuronal net numbers that encapsulate parvalbumin⁺ neurons in the hippocampus were observed following chronic ECS.
Our findings indicate that age is a key variable in determining the nature of chronic ECS-evoked molecular and cellular changes in the hippocampus. This raises the intriguing possibility that chronic ECS may recruit distinct, as well as overlapping, mechanisms to drive antidepressant-like behavioral changes in an age-dependent manner.
电惊厥疗法常用于治疗抵抗性和老年抑郁症。然而，识别慢性电惊厥（ECS）靶点的临床前研究主要集中在年轻成年动物模型上。鉴于慢性 ECS 自身所涉及的行为效应的潜在转录、神经发生和神经可塑性机制表现出年龄依赖性调节，因此尚不清楚慢性 ECS 的分子和细胞靶点是否随年龄而变化。
我们对年轻成年（2-3 个月）和中年（12-13 个月）雄性 Sprague Dawley 大鼠进行假手术或慢性 ECS，并评估其类似绝望的行为、海马基因表达、海马神经发生以及细胞外基质、reelin 和神经周细胞网络数量的神经可塑性变化。
慢性 ECS 减轻了两个年龄段的类似绝望行为，同时伴随着活性依赖性和营养因子基因表达的重叠和独特变化。尽管慢性 ECS 对两个年龄段的静止神经祖细胞数量有相似的影响，但年轻成年时海马祖细胞增殖的最终增加幅度要大得多。我们注意到，只有在年轻成年时，慢性 ECS 后 reelin⁺细胞数量下降。相比之下，慢性 ECS 后，海马中包裹 parvalbumin⁺神经元的神经周细胞网络数量出现了一致且显著的溶解，而这种溶解在年龄上没有变化。
我们的研究结果表明，年龄是决定慢性 ECS 诱发海马分子和细胞变化性质的关键变量。这提出了一个有趣的可能性，即慢性 ECS 可能以年龄依赖的方式招募不同的、重叠的机制来驱动抗抑郁样行为变化。
