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Neurobiol Aging. 2018 Nov;71:241-254. doi: 10.1016/j.neurobiolaging.2018.08.002. Epub 2018 Aug 7.

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

Author information

1
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
2
Division of Neurology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
3
Undergraduate Program in Neuroscience, Vanderbilt University, Nashville, TN, USA.
4
Interdisciplinary Graduate Program, Vanderbilt University, Nashville, TN, USA.
5
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: Fiona.harrison@vanderbilt.edu.

Abstract

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 wild-type 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 APPSWE/PSEN1dE9 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.

KEYWORDS:

Ascorbate; Behavior; GLT-1; Glutamate; Seizure; Vitamin C

PMID:
30172223
PMCID:
PMC6162152
[Available on 2019-11-01]
DOI:
10.1016/j.neurobiolaging.2018.08.002

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