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

Abstract

AbstractAstrocytes are abundant and heterogeneous cell types in the CNS [1]. They promote neuronal health and survival and protect neurons from glutamate-induced excitotoxicity. In the spinal cord, astrocytes are present in both the dorsal horn (DH) and ventral horns (VH). However, only motor neurons in the VH are highly vulnerable to glutamate excitotoxicity. We hypothesize that the preferential vulnerability of motor neurons may underlie their spatial confinement to the VH, where astrocytes are differentially equipped with glutamate-handling machinery. With aging, glutamate excitotoxicity increases, suggesting compromised astrocytic glutamate handling. We tested our hypotheses by comparing astrocytic morphology, expression of glutamate transporters, and glutamate uptake function in the DH and VH using immunohistochemical staining, western blotting, and whole-cell patch-clamp electrophysiology. We found a global reduction in the numerical density and astroglial coverage in the spinal cord, with a prominent decline in the VH with aging. Astrocytic glutamate transporters, Excitatory amino acid transporter 1 (EAAT1) and Excitatory amino acid transporter 2 (EAAT2), show an overall reduction in expression with aging, with a more progressive decrease in the VH than DH. We performed whole-cell patch-clamp studies on DH and VH astrocytes to assess the functional outcome of the altered expression of EAATs with aging. Both VH and DH astrocytes showed a dramatic decline in glutamate uptake currents with aging, suggesting compromised glutamate handling in aging astrocytes. Our study suggests that astrocytes in the DH and VH undergo differential changes with aging, exhibiting compromised glutamate handling properties, which may be one of the key contributors to the late onset of neurodegenerative disorders.