A Cytotoxic, Co-operative Interaction Between Energy Deprivation and Glutamate Release From System x_c⁻Mediates Aglycemic Neuronal Cell Death

Abstract

The astrocyte cystine/glutamate antiporter (system xc−) contributes substantially to the excitotoxic neuronal cell death facilitated by glucose deprivation. The purpose of this study was to determine the mechanism by which this occurred. Using pure astrocyte cultures, as well as, mixed cortical cell cultures containing both neurons and astrocytes, we found that neither an enhancement in system xc− expression nor activity underlies the excitotoxic effects of aglycemia. In addition, using three separate bioassays, we demonstrate no change in the ability of glucose-deprived astrocytes—either cultured alone or with neurons—to remove glutamate from the extracellular space. Instead, we demonstrate that glucose-deprived cultures are 2 to 3 times more sensitive to the killing effects of glutamate or N-methyl-D-aspartate when compared with their glucose-containing controls. Hence, our results are consistent with the weak excitotoxic hypothesis such that a bioenergetic deficiency, which is measureable in our mixed but not astrocyte cultures, allows normally innocuous concentrations of glutamate to become excitotoxic. Adding to the burgeoning literature detailing the contribution of astrocytes to neuronal injury, we conclude that under our experimental paradigm, a cytotoxic, co-operative interaction between energy deprivation and glutamate release from astrocyte system xc− mediates aglycemic neuronal cell death.

Decreased epileptogenesis in mice lacking the System xc− transporter occurs in association with a reduction in AMPA receptor subunit GluA1

“…35). 40 Lending credence to this interpretation are the findings that a reduction in GABAergic inhibition 41,42 and an increase in extracellular Glu and Glu receptor levels 43,44 are associated with PTZ-kindling in rodents. These findings complement studies demonstrating an incontrovertible role for Sx c − in glioma-associated epilepsy in both mice and man.…”

“…However, present data suggest that in vivo glutamatergic tone-maintained in large part by nonvesicular release of Glu by Sx c −10-12 -may be enough to dysregulate excitatory signaling in wild-type mice, as we previously documented in an in vitro paradigm of hypoglycemic neuronal cell death. 40 Lending credence to this interpretation are the findings that a reduction in GABAergic inhibition 41,42 and an increase in extracellular Glu and Glu receptor levels 43,44 are associated with PTZ-kindling in rodents. Conversely, a decrease in ambient, extracellular Glu levels has been reported in mice lacking Sx c − .…”

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

“…As stated before, another AD hallmark is hypoglycemia. Removal of glucose in mixed astrocyte-neuron cell cultures leads to a glycemic neuronal injury and death (Thorn et al, 2015). However, the neuronal death observed in glucose deprivation conditions is not connected to energy failure but most likely tied to glutamate accumulation in the synaptic cleft (Jackman et al, 2012).…”

“…As these processes are tightly linked, the dysfunction of one is likely to mediate the function of the other system, for the benefit or damage. Upon glucose deprivation in cultured astrocytes, xCT protein expression rose in a time-dependent matter (Thorn et al, 2015).…”

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

“…However, many researchers hold opposing views and state that activated system xc- can exacerbate ischemic cerebral injury due to increased glutamate. In their studies, xCT was expressed in significant concentrations in astrocytes in the mouse brain ( Jackman et al, 2012 ; Thorn et al, 2015 ; Ottestad-Hansen et al, 2018 ). Increased activity of system xc-( Soria et al, 2014 ) promoted the release of glutamate which may contribute to excitotoxicity in pathological situations (e.g., oxygen and glucose deprivation), leading to neuronal death ( Thorn et al, 2015 ; Ottestad-Hansen et al, 2018 ).…”