Altered glutamate clearance in ascorbate deficient mice increases seizure susceptibility and contributes to cognitive impairment in APP/PSEN1 mice

NEUROBIOLOGY OF AGING

卷:71

Article

Mi, Deborah J.¹  Dixit, Shilpy¹  Warner, Timothy A.²  Kennard, John A.¹  Scharf, Daniel A.³  Kessler, Eric S.³  Moore, Lisa M.³  Consoli, David C.⁴  Bown, Corey W.⁴  Eugene, Angeline J.³  Kang, Jing-Qiong²  Harrison, Fiona E.¹ 

[1] Vanderbilt Univ, Med Ctr, Dept Med, Div Diabet Endocrinol & Metab, 221 Kirkland Hall, Nashville, TN 37235 USA

[2] Vanderbilt Univ, Med Ctr, Dept Med, Div Neurol, 221 Kirkland Hall, Nashville, TN 37235 USA

[3] Vanderbilt Univ, Undergrad Program Neurosci, 221 Kirkland Hall, Nashville, TN 37235 USA

[4] Vanderbilt Univ, Interdisciplinary Grad Program, 221 Kirkland Hall, Nashville, TN 37235 USA

关键词: Vitamin C;    Ascorbate;    GLT-1;    Glutamate;    Seizure;    Behavior;   

DOI  :  10.1016/j.neurobiolaging.2018.08.002

来源: Elsevier

【 摘 要 】

Ascorbate (vitamin C) is critical as a first line of defense antioxidant within the brain, and specifically within the synapse. Ascorbate is released by astrocytes during glutamate clearance and disruption of this exchange mechanism may be critical in mediating glutamate toxicity within the synapse. This is likely even more critical in neurodegenerative disorders with associated excitotoxicity and seizures, in particular Alzheimer's disease, in which ascorbate levels are often low. Using Gulo(-/-) mice that are dependent on dietary ascorbate, we established that low brain ascorbate increased sensitivity to kainic acid as measured via behavioral observations, electroencephalography (EEG) measurements, and altered regulation of several glutamatergic system genes. Kainic acid-induced immobility was improved in wildtype mice following treatment with ceftriaxone, which upregulates glutamate transporter GLT-1. The same effect was not observed in ascorbate-deficient mice in which sufficient ascorbate is not available for release. A single, mild seizure event was sufficient to disrupt performance in the water maze in low-ascorbate mice and in APP(SWE)/PSEN1(dE9) mice. Together, the data support the critical role of brain ascorbate in maintaining protection during glutamatergic hyperexcitation events, including seizures. The study further supports a role for mild, subclinical seizures in cognitive decline in Alzheimer's disease. (C) 2018 Elsevier Inc. All rights reserved.

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