Neurovascular Pathophysiology, Cardiovascular Risk Factor and Brain Function Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (C.T.-L., M.I.C., A.G.-C., S.V.-R., T.J.-F., F.J.d.C.-M., O.H., M.A.M.).
Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina (C.T.-L., M.I.C., A.G.-C., J.d.l.P., S.V.-R., T.J.-F., F.J.d.C.-M., I.L., M.A.M.), Universidad Complutense de Madrid (UCM), Spain.
Stroke. 2023 Oct;54(10):2652-2665. doi: 10.1161/STROKEAHA.123.043516. Epub 2023 Sep 11.
Cognitive dysfunction is a frequent stroke sequela, but its pathogenesis and treatment remain unresolved. Involvement of aberrant hippocampal neurogenesis and maladaptive circuitry remodeling has been proposed, but their mechanisms are unknown. Our aim was to evaluate potential underlying molecular/cellular events implicated.
Stroke was induced by permanent occlusion of the middle cerebral artery occlusion in 2-month-old C57BL/6 male mice. Hippocampal metabolites/neurotransmitters were analyzed longitudinally by in vivo magnetic resonance spectroscopy. Cognitive function was evaluated with the contextual fear conditioning test. Microglia, astrocytes, neuroblasts, interneurons, γ-aminobutyric acid (GABA), and c-fos were analyzed by immunofluorescence.
Approximately 50% of mice exhibited progressive post-middle cerebral artery occlusion cognitive impairment. Notably, immature hippocampal neurons in the impaired group displayed more severe aberrant phenotypes than those from the nonimpaired group. Using magnetic resonance spectroscopy, significant bilateral changes in hippocampal metabolites, such as myo-inositol or N-acetylaspartic acid, were found that correlated, respectively, with numbers of glia and immature neuroblasts in the ischemic group. Importantly, some metabolites were specifically altered in the ipsilateral hippocampus suggesting its involvement in aberrant hippocampal neurogenesis and remodeling processes. Specifically, middle cerebral artery occlusion animals with higher hippocampal GABA levels displayed worse cognitive outcome. Implication of GABA in this setting was supported by the amelioration of ischemia-induced memory deficits and aberrant hippocampal neurogenesis after blocking pharmacologically GABAergic neurotransmission, an intervention which was ineffective when neurogenesis was inhibited. These data suggest that GABA exerts its detrimental effect, at least partly, by affecting morphology and integration of newborn neurons into the hippocampal circuits.
Hippocampal GABAergic neurotransmission could be considered a novel diagnostic and therapeutic target for poststroke cognitive impairment.
认知功能障碍是中风的常见后遗症，但发病机制和治疗方法仍未解决。已经提出了异常海马神经发生和适应性回路重塑的参与，但它们的机制尚不清楚。我们的目的是评估潜在的相关分子/细胞事件。
通过永久性阻断大脑中动脉闭塞在 2 个月大的 C57BL/6 雄性小鼠中诱导中风。通过体内磁共振波谱分析纵向分析海马代谢物/神经递质。通过情景性恐惧条件测试评估认知功能。通过免疫荧光分析小胶质细胞、星形胶质细胞、神经母细胞、中间神经元、γ-氨基丁酸 (GABA) 和 c-fos。
大约 50%的小鼠表现出进行性中风后认知障碍。值得注意的是，受损组的不成熟海马神经元表现出比非受损组更严重的异常表型。使用磁共振波谱，发现海马代谢物（如肌醇或 N-乙酰天冬氨酸）的双侧变化显著，这些变化分别与缺血组中的胶质细胞和不成熟神经母细胞的数量相关。重要的是，一些代谢物在同侧海马中特异性改变，表明其参与异常海马神经发生和重塑过程。具体来说，海马 GABA 水平较高的大脑中动脉闭塞动物表现出更差的认知结果。GABA 在这种情况下的作用得到了支持，因为阻断 GABA 能神经传递的药理学干预改善了缺血引起的记忆缺陷和异常海马神经发生，而当神经发生被抑制时，这种干预无效。这些数据表明 GABA 通过影响新生神经元的形态和整合到海马回路中发挥其有害作用，至少部分如此。
海马 GABA 能神经传递可以被认为是中风后认知障碍的一个新的诊断和治疗靶点。
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