Hasan Smn, Wan-Yan-Chan D, Hogan A, Ivany K, Noel R, Clark C, Waye S, Bambico F R
Department of Psychology, Memorial University of Newfoundland and Labrador, Newfoundland and Labrador, A1B3X9, Canada.
Neurosci Appl. 2023 Dec 1;3:103928. doi: 10.1016/j.nsa.2023.103928. eCollection 2024.
Depression is a common mood disorder with a multifaceted, complex pathophysiology. An abnormal level of corticosteroids in the brain can cause structural change in the hippocampus. It may cause an imbalance in calcium homeostasis leading to functional impairment in the activity of the voltage-insensitive, small conductance, calcium-activated potassium channel (SKC). Deficit in the longevity protein klotho is also implicated in stress-induced depression. We ascertained whether chronic activation of SKCs can cause age-dependent depressive-like behavior and cognitive deficits, accompanied by disturbances in klotho concentration. We tested the effect of repeated activation of SKCs by the potent SKC agonist, 1-EBIO (1.0 mg/kg, IP, once daily for 15 days) in young (3 months) and mid-life (12 months) male BALB/c mice. We conducted a battery of behavioral tests to investigate depressive-like behavior and cognitive functions. Then, we used an enzyme-linked immunosorbent assay (ELISA) on brain homogenates to determine the change in total klotho concentration in the prefrontal cortex, hippocampus, and dorsal raphe. We found that chronic 1-EBIO treatment decreased locomotor activity, sucrose preference, and alternation index in an age-dependent manner. The drug does not affect stress-coping behavior in the forced swim test. The behavioral deficits were accompanied by a significant decrease in total klotho concentration in the hippocampus but not in the prefrontal cortex or dorsal raphe, observed in an age-dependent manner. Based on these results, we surmise that chronic activation of SKCs results in concurrent cognitive and depressive-like phenotypes in mid-aged mice. Therefore, this could represent a putative therapeutic target for age-related psycho-affective disorders.
抑郁症是一种常见的情绪障碍，其病理生理学具有多方面且复杂的特点。大脑中皮质类固醇水平异常可导致海马体结构改变。这可能会导致钙稳态失衡，进而导致电压不敏感、小电导、钙激活钾通道（SKC）的活性出现功能障碍。长寿蛋白α-klotho缺乏也与应激诱导的抑郁症有关。我们确定SKC的慢性激活是否会导致年龄依赖性的抑郁样行为和认知缺陷，并伴有α-klotho浓度紊乱。我们测试了强效SKC激动剂1-EBIO（1.0毫克/千克，腹腔注射，每天一次，共15天）对年轻（3个月）和中年（12个月）雄性BALB/c小鼠重复激活SKC的效果。我们进行了一系列行为测试来研究抑郁样行为和认知功能。然后，我们对脑匀浆进行酶联免疫吸附测定（ELISA），以确定前额叶皮质、海马体和中缝背核中总α-klotho浓度的变化。我们发现，慢性1-EBIO治疗以年龄依赖性方式降低了运动活性、蔗糖偏好和交替指数。该药物在强迫游泳试验中不影响应激应对行为。行为缺陷伴随着海马体中总α-klotho浓度的显著降低，但在前额叶皮质或中缝背核中未观察到，且呈现年龄依赖性。基于这些结果，我们推测SKC的慢性激活会导致中年小鼠同时出现认知和抑郁样表型。因此，这可能代表了与年龄相关的心理情感障碍的一个潜在治疗靶点。
