Abstract
Brain aging is a natural process that involves structural and functional changes that lead to cognitive decline, even in healthy subjects. This detriment has been associated with NMDA receptor (NMDAR) hypofunction because of a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear whether D-serine supplementation could be used as an intervention to reduce or reverse age-related brain alterations. In the present work, we aimed to analyze the D-serine effect on aging-associated alterations in cellular and large-scale brain systems that could support cognitive flexibility in rats. We found that D-serine supplementation reverts the age-related decline in cognitive flexibility, frontal dendritic spine density, and partially restored large-scale functional connectivity without inducing nephrotoxicity; instead, D-serine restored the thickness of the renal epithelial cells that were affected by age. Our results suggest that D-serine could be used as a therapeutic target to reverse age-related brain alterations.
Footnotes
The authors declare no competing financial interests.
This work was supported by grants from Consejo Nacional de Ciencia y Tecnologia (CONACyT) Ciencia de Frontera 171874 (to M.L.H.), CONACyT Problemas Nacionales 2132 (to N.H.C.), PAPIIT-DGAPA IA208120 (to M.L.H.), PAPIIT-DGAPA IA208022 (to M.L.H.), CONACYT Ciencia Básica A1-S-8686 (to G.R.-P.), and UNAM-DGAPA PAPIIT IN201121 (to G.R.-P.). L.N.-G. and P.A. are doctoral students from the Programa de Doctorado en Biomedicina, from Universidad Autónoma de Querétaro, and received CONACyT Fellowships 472970 and 815419. I.C.-V. is a doctoral student from the Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), and received the CONACyT Fellowship 786125. F.H.-R. and B.V.-P. are master students from the Programa de Maestría en Ciencias (Neurobiología) from UNAM and received CONACyT Fellowships 778405 and 778596.
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