Aging-related changes in expression and function of glutamate transporters in rat spinal cord astrocytes

Astrocytes are the most abundant and heterogeneous cells in the central nervous system. They not only promote neuronal health and survival but also protect neurons from glutamate-induced excitotoxic insults. In the spinal cord, astrocytes are present in both the dorsal horn (DH) and ventral horns (VH) however only motor neurons in the ventral horn are highly vulnerable to glutamate excitotoxicity. We hypothesize that the preferential vulnerability of motor neurons may underlie their spatial confinement into the ventral horn wherein astrocytes are differentially equipped with glutamate handling machinery. With aging, this glutamate excitotoxicity increases suggesting a compromised astrocytic glutamate handling as a function of aging. We addressed these hypotheses by comparing astrocytic morphology, expression of glutamate transports, and glutamate uptake function in dorsal and ventral horns using immunohistochemical staining, western blotting, and whole-cell patch-clamp electrophysiology. Our results suggest a global reduction in the numerical density and astroglial coverage of in spinal cord, with the most prominent decline in the ventral horn with aging. Astrocytic glutamate transporter EAAT1 and EAAT2 show an overall reduction in expression with aging. However, the ventral horn showed a progressive decrease compared to the dorsal horn. To assess the functional outcome of the altered expression of EAATs with aging we performed whole-cell patch-clamp studies in dorsal and ventral horn astrocytes in different age groups. Both ventral and dorsal horn astrocytes showed a dramatic decline in the glutamate uptake currents with aging, suggesting a compromised glutamate handling by aging astrocytes. Our study suggests that astrocytes in the dorsal and ventral horn undergo differential changes with aging leading to compromise in their glutamate handling properties. These age and region-associated alterations in extracellular glutamate regulation through astrocytic glutamate transporters may be key contributors to the late onset of neurodegenerative disorders including sporadic ALS. ### Competing Interest Statement The authors have declared no competing interest.