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 N-methyl-D-aspartate receptor (NMDAR) hypofunction due to a reduction in the brain levels of D-serine, the endogenous NMDAR co-agonist. However, it is not clear if 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.SIGNIFICANT STATEMENTAge-related behavioral changes in cognitive performance occur as a physiological process of aging. Then, it is important to explore possible therapeutics to decrease, retard or reverse aging effects on the brain. NMDA receptor hypofunction contributes to the aging-associated cognitive decline. In the aged brain, there is a reduction in the brain levels of the NMDAR co-agonist, D-Serine. However, it is unclear if chronic D-serine supplementation could revert the age-detriment in brain functions. Our results show that D-serine supplementation reverts the age-associated decrease in cognitive flexibility, functional brain connectivity, and neuronal morphology. Our findings raise the possibility that restoring the brain levels of D-serine could be used as a therapeutic target to recover brain alterations associated with aging.
ABSTRACT
Atrazine (ATR; 2-chloro-4-ethylamino-6-isopropylamino-s-triazine) is an herbicide widely used to kill annual grasses and broadleaf weeds in crops such as corn, sorghum, and sugarcane. Studies in rodents have shown that chronic ATR exposure is associated with alterations in the nigrostriatal dopaminergic pathway such as hyperactivity, decreased striatal dopamine levels, and diminished numbers of tyrosine hydroxylase positive cells in substantia nigra pars compacta. However, the effects of ATR on neurotransmitters such as GABA and glutamate have been scarcely studied. To evaluate the impact of ATR on motor and anxiety tasks, tissue levels of GABA, glutamate, glutamine, and extracellular and potassium-evoked release of glutamate in the striatum, we daily exposed Sprague-Dawley male rats to 1 or 10 mg ATR/kg of body weight for 12-14 months. As previously reported, chronic ATR exposure causes hyperactivity in the group exposed to 10 mg ATR/kg and increased anxiety in both groups exposed to ATR. GABA, glutamate, and glutamine levels were differentially altered in brain regions related to nigrostriatal and mesolimbic systems, the amygdala, and the prefrontal cortex. The groups exposed to 10 mg ATR/kg showed increased extracellular levels and release of glutamate in the striatum. These neurochemical alterations could underlie the behavioral changes observed in rats. These results indicate that chronic exposure to the herbicide ATR disrupts the neurochemistry of several brain structures and could be a risk factor for the development of neurodegenerative diseases.
