Non-cell autonomous influence of the astrocyte system xc- on hypoglycaemic neuronal cell death.
Despite longstanding evidence that hypoglycaemic neuronal injury is mediated by glutamate excitotoxicity, the cellular and molecular mechanisms involved remain incompletely defined. Here, we demonstrate that the excitotoxic neuronal death that follows GD (glucose deprivation) is initiated by glutamate extruded from astrocytes via system xc---an amino acid transporter that imports L-cystine and exports L-glutamate. Specifically, we find that depriving mixed cortical cell cultures of glucose for up to 8 h injures neurons, but not astrocytes. Neuronal death is prevented by ionotropic glutamate receptor antagonism and is partially sensitive to tetanus toxin. Removal of amino acids during the deprivation period prevents--whereas addition of L-cystine restores--GD-induced neuronal death, implicating the cystine/glutamate antiporter, system xc-. Indeed, drugs known to inhibit system xc- ameliorate GD-induced neuronal death. Further, a dramatic reduction in neuronal death is observed in chimaeric cultures consisting of neurons derived from WT (wild-type) mice plated on top of astrocytes derived from sut mice, which harbour a naturally occurring null mutation in the gene (Slc7a11) that encodes the substrate-specific light chain of system xc- (xCT). Finally, enhancement of astrocytic system xc- expression and function via IL-1β (interleukin-1β) exposure potentiates hypoglycaemic neuronal death, the process of which is prevented by removal of l-cystine and/or addition of system xc- inhibitors. Thus, under the conditions of GD, our studies demonstrate that astrocytes, via system xc-, have a direct, non-cell autonomous effect on cortical neuron survival.
Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA.
Nicole A
NA
Jackman
Shannon E
SE
Melchior
James A
JA
Hewett
Sandra J
SJ
Hewett
D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002450:Cell Communication / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D018920:Coculture Techniques; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction
D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse; D018698:Glutamic Acid; D005947:Glucose