Hao Keke, Chen Fashuai, Xu Shilin, Xiong Ying, Xu Rui, Huang Huan, Shu Chang, Lv Yisheng, Wang Gaohua, Wang Huiling
Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Psychiatry, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Transl Psychiatry. 2025 Mar 30;15(1):112. doi: 10.1038/s41398-025-03318-2.
Maternal separation (MS) during early life can induce behaviors in adult animals that resemble those seen in schizophrenia, manifesting cognitive deficits. These cognitive deficits may be indicative of oxidative stress linked to mitochondrial dysfunction. However, there is limited understanding of the molecular mechanisms regulating mitochondria in neural circuits that govern cognitive impairment relevant to schizophrenia, and their impact on neuronal structure and function. A 24-h MS rat model was utilized to simulate features associated with schizophrenia. Schizophrenia-associated behaviors and cognitive impairment were assessed using the open field test, pre-pulse inhibition, novel object recognition test, and Barnes maze test. The levels of mitochondrial proteins were measured using western blot analysis. Additionally, alterations in mitochondrial morphology, reduced hippocampal neuronal spine density, and impaired LTP in the hippocampus were observed. Nicotinamide (NAM) supplementation, administration of honokiol (HNK) (a SIRT3 activator), or overexpression of SIRT3 could inhibit cognitive deficits and cellular dysfunction. Conversely, administration of 3-TYP (a SIRT3 inhibitor) or knocking down SIRT3 expression in control rats led to deficits in behavioral and hippocampal neuronal phenotype. Our results suggest a causal role for the NAD+/SIRT3 axis in modulating cognitive behaviors via effects on hippocampal neuronal synaptic plasticity. The NAD+/SIRT3 axis could be a promising therapeutic target for addressing cognitive dysfunctions, such as those seen in schizophrenia.
早年经历的母婴分离（MS）可诱发成年动物出现类似精神分裂症的行为，表现为认知缺陷。这些认知缺陷可能表明与线粒体功能障碍相关的氧化应激。然而，对于在与精神分裂症相关的认知障碍的神经回路中调节线粒体的分子机制，以及它们对神经元结构和功能的影响，我们的了解有限。利用24小时MS大鼠模型来模拟与精神分裂症相关的特征。使用旷场试验、前脉冲抑制、新物体识别试验和巴恩斯迷宫试验评估与精神分裂症相关的行为和认知障碍。使用蛋白质免疫印迹分析测量线粒体蛋白水平。此外，还观察到线粒体形态的改变、海马神经元棘密度降低以及海马长时程增强受损。补充烟酰胺（NAM）、给予厚朴酚（HNK）（一种SIRT3激活剂）或过表达SIRT3可抑制认知缺陷和细胞功能障碍。相反，给予3-TYP（一种SIRT3抑制剂）或敲低对照大鼠中的SIRT3表达会导致行为和海马神经元表型缺陷。我们的结果表明，NAD + /SIRT3轴通过影响海马神经元突触可塑性在调节认知行为中起因果作用。NAD + /SIRT3轴可能是解决认知功能障碍（如精神分裂症中所见）的一个有前景的治疗靶点。
