Deficient glucose and glutamine metabolism in Aralar/AGC1/Slc25a12 knockout mice contributes to altered visual function

Mol Vis. 2016 Oct 12;22:1198-1212. eCollection 2016.


Purpose: To characterize the vision phenotype of mice lacking Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier mutated in global cerebral hypomyelination (OMIM 612949).

Methods: We tested overnight dark-adapted control and aralar-deficient mice for the standard full electroretinogram (ERG) response. The metabolic stress of dark-adaptation was reduced by 5 min illumination after which the ERG response was monitored in darkness. We used the electrical response to two identical saturating light flashes (paired-flash stimulation) to isolate the inner retina and photoreceptor responses. Retinal morphology was examined with hematoxylin and eosin staining, immunohistochemistry of antibodies against retinal cells, and 4',6-diamidino-2-phenylindole (DAPI) labeling.

Results: Aralar plays a pivotal role in retina metabolism as aralar provides de novo synthesis pathway for glutamine, protects glutamate from oxidation, and is required for efficient glucose oxidative metabolism. Aralar-deficient mice are not blind as their retinas have light-evoked activity. However, we report an approximate 50% decrease in the ERG amplitude response in the light-evoked activity of dark-adapted retinas from aralar-deficient mice, in spite of normal retina histology. The defective response is partly reversed by exposure to a brief illumination period, which lowers the metabolic stress of dark-adaptation. The metabolic stress and ERG alteration takes place primarily in photoreceptors, but the response to two flashes applied in fast succession also revealed an alteration in synaptic transmission consistent with an imbalance of glutamate and an energy deficit in the inner retina neurons.

Conclusions: We propose that compromised glucose oxidation and altered glutamine and glutamate metabolism in the absence of aralar are responsible for the phenotype reported.

MeSH terms

  • Aggrecans / physiology*
  • Amino Acid Transport Systems, Acidic / deficiency
  • Amino Acid Transport Systems, Acidic / metabolism
  • Animals
  • Antiporters / deficiency
  • Antiporters / metabolism
  • Dark Adaptation
  • Electroretinography
  • Glucose / metabolism*
  • Glutamine / metabolism*
  • Hereditary Central Nervous System Demyelinating Diseases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Diseases / metabolism
  • Mitochondrial Membrane Transport Proteins / physiology*
  • Photic Stimulation
  • Psychomotor Disorders / metabolism
  • Retina / metabolism*
  • Retina / physiopathology
  • Retinal Bipolar Cells / physiology
  • Synaptic Transmission
  • Vision Disorders / metabolism*
  • Vision Disorders / physiopathology


  • Acan protein, mouse
  • Aggrecans
  • Amino Acid Transport Systems, Acidic
  • Antiporters
  • Mitochondrial Membrane Transport Proteins
  • Slc25a12 protein, mouse
  • Glutamine
  • Glucose

Supplementary concepts

  • Hypomyelination, Global Cerebral