Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimer's disease are closely associated with mitochondrial dysfunction, increased reactive oxygen species, neuroinflammation, and astrogliosis. This study investigated the effects of decreased mitochondrial antioxidant response specifically in astrocytes on cognitive performance and neuronal function in C57BL/6J mice using a tamoxifen-inducible astrocyte-specific knockout of manganese superoxide dismutase (aSOD2-KO), a mitochondrial matrix antioxidant that detoxifies superoxide generated during mitochondrial respiration. We reduced astrocyte SOD2 levels in male and female mice at 11–12 months of age and tested in an automated home cage (PhenoTyper) apparatus for diurnal patterns, spatial learning, and memory function at 15 months of age. aSOD2-KO impaired hippocampal-dependent spatial working memory and decreased cognitive flexibility in the reversal phase of the testing paradigm in males. Female aSOD2-KO showed no learning and memory deficits compared with age-matched controls despite significant reduction in hippocampal SOD2 expression. aSOD2-KO males further showed decreased hippocampal long-term potentiation, but paired-pulse facilitation was unaffected. Levels of d-serine, an NMDA receptor coagonist, were also reduced in aSOD2-KO mice, but female knockouts showed a compensatory increase in serine racemase expression. Furthermore, aSOD2-KO mice demonstrated increased density of astrocytes, indicative of astrogliosis, in the hippocampus compared with age-matched controls. These data demonstrate that reduction in mitochondrial antioxidant stress response in astrocytes recapitulates age-related deficits in cognitive function, d-serine availability, and astrogliosis. Therefore, improving astrocyte mitochondrial homeostasis may provide a therapeutic target for intervention for cognitive impairment in aging.

SIGNIFICANCE STATEMENT Diminished antioxidant response is associated with increased astrogliosis in aging and in Alzheimer's disease. Manganese superoxide dismutase (SOD2) is an antioxidant in the mitochondrial matrix that detoxifies superoxide and maintains mitochondrial homeostasis. We show that astrocytic ablation of SOD2 impairs hippocampal-dependent plasticity in spatial working memory, reduces long-term potentiation of hippocampal neurons and levels of the neuromodulator d-serine, and increases astrogliosis, consistent with defects in advanced aging and Alzheimer's disease. Our data provide strong evidence for sex-specific effects of astrocytic SOD2 functions in age-related cognitive dysfunction.

认知能力下降是衰老和神经退行性疾病（例如阿尔茨海默病）的一个方面，与线粒体功能障碍、活性氧增加、神经炎症和星形胶质细胞增多症密切相关。本研究使用他莫昔芬诱导的星形胶质细胞特异性敲除锰超氧化物歧化酶 (aSOD2-KO)（一种解毒超氧化物的线粒体基质抗氧化剂），研究了星形胶质细胞中线粒体抗氧化反应降低对 C57BL/6J 小鼠认知表现和神经元功能的影响。线粒体呼吸过程中产生。我们降低了 11-12 月龄雄性和雌性小鼠的星形胶质细胞 SOD2 水平，并在 15 月龄时在自动化家用笼 (PhenoTyper) 装置中测试了昼夜模式、空间学习和记忆功能。 aSOD2-KO 损害了男性海马依赖性空间工作记忆，并降低了男性测试范式逆转阶段的认知灵活性。尽管海马 SOD2 表达显着降低，但与年龄匹配的对照组相比，女性 aSOD2-KO 没有表现出学习和记忆缺陷。 aSOD2-KO 雄性进一步表现出海马长时程增强能力下降，但配对脉冲易化不受影响。 aSOD2-KO 小鼠中，NMDA 受体共激动剂 d-丝氨酸的水平也降低，但雌性基因敲除小鼠显示丝氨酸消旋酶表达补偿性增加。此外，与年龄匹配的对照组相比，aSOD2-KO小鼠的海马区星形胶质细胞密度增加，表明存在星形胶质细胞增生。这些数据表明，星形胶质细胞中线粒体抗氧化应激反应的减少概括了与年龄相关的认知功能、d-丝氨酸可用性和星形胶质细胞增生的缺陷。 因此，改善星形胶质细胞线粒体稳态可能为干预衰老认知障碍提供治疗靶点。

意义声明抗氧化反应减弱与衰老和阿尔茨海默病中星形胶质细胞增多有关。锰超氧化物歧化酶 (SOD2) 是线粒体基质中的一种抗氧化剂，可解毒超氧化物并维持线粒体稳态。我们发现，星形胶质细胞消融 SOD2 会损害空间工作记忆中海马依赖性可塑性，降低海马神经元的长期增强和神经调节剂 d-丝氨酸的水平，并增加星形胶质细胞增生，这与晚期衰老和阿尔茨海默病的缺陷一致。我们的数据为星形胶质细胞 SOD2 功能对年龄相关认知功能障碍的性别特异性影响提供了强有力的证据。