NHC Key Laboratory of Diagnosis and Treatment on Brain Functional Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
Acta Neuropathol Commun. 2023 Apr 3;11(1):59. doi: 10.1186/s40478-023-01545-6.
Carbonic Anhydrase 1 (CAR1) is a zinc-metalloenzyme that catalyzes the hydration of carbon dioxide, and the alteration of CAR1 has been implicated in neuropsychiatric disorders. However, the mechanism underlying the role of CAR1 in major depressive disorder (MDD) remains largely unknown. In this study, we report the decreased level of CAR1 in MDD patients and depression-like model rodents. We found that CAR1 is expressed in hippocampal astrocytes and CAR1 regulates extracellular bicarbonate concentration and pH value in the partial hilus. Ablation of the CAR1 gene increased the activity of granule cells via decreasing their miniature inhibitory postsynaptic currents (mIPSC), and caused depression-like behaviors in CAR1-knockout mice. Astrocytic CAR1 expression rescued the deficits in mIPSCs of granule cells and reduced depression-like behaviors in CAR1 deficient mice. Furthermore, pharmacological activation of CAR1 and overexpression of CAR1 in the ventral hippocampus of mice improved depressive behaviors. These findings uncover a critical role of CAR1 in the MDD pathogenesis and its therapeutic potential.
碳酸酐酶 1（CAR1）是一种锌金属酶，可催化二氧化碳的水合作用，CAR1 的改变与神经精神疾病有关。然而，CAR1 在重度抑郁症（MDD）中的作用机制在很大程度上尚不清楚。在这项研究中，我们报告了 MDD 患者和抑郁样模型啮齿动物中 CAR1 水平降低。我们发现 CAR1 在海马星形胶质细胞中表达，CAR1 调节部分门区的细胞外重碳酸盐浓度和 pH 值。CAR1 基因缺失会通过减少颗粒细胞的微小抑制性突触后电流（mIPSC）来增加颗粒细胞的活性，并且会导致 CAR1 敲除小鼠出现抑郁样行为。星形胶质细胞 CAR1 的表达挽救了 CAR1 缺失小鼠颗粒细胞中 mIPSCs 的缺陷，并减少了其抑郁样行为。此外，CAR1 的药理学激活和在小鼠腹侧海马中的过表达改善了抑郁行为。这些发现揭示了 CAR1 在 MDD 发病机制及其治疗潜力中的关键作用。
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