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Publication
Altered glutamate clearance in ascorbate deficient mice increases seizure
susceptibility and contributes to cognitive impairment in APP/PSEN1 mice.
Authors Mi DJ, Dixit S, Warner TA, Kennard JA, Scharf DA, Kessler ES, Moore LM, Consoli
DC, Bown CW, Eugene AJ, Kang JQ, Harrison FE
Submitted By Submitted Externally on 9/24/2018
Status Published
Journal Neurobiology of aging
Year 2018
Date Published 8/1/2018
Volume : Pages 71 : 241 - 254
PubMed Reference 30172223
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.




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