Sex-Specific Life Course Changes in the Neuro-Metabolic Phenotype of Glut3 Null Heterozygous Mice: Ketogenic Diet Ameliorates Electroencephalographic Seizures and Improves Sociability

Endocrinology. 2017 Apr 1;158(4):936-949. doi: 10.1210/en.2016-1816.


We tested the hypothesis that exposure of glut3+/- mice to a ketogenic diet ameliorates autism-like features, which include aberrant behavior and electrographic seizures. We first investigated the life course sex-specific changes in basal plasma-cerebrospinal fluid (CSF)-brain metabolic profile, brain glucose transport/uptake, glucose and monocarboxylate transporter proteins, and adenosine triphosphate (ATP) in the presence or absence of systemic insulin administration. Glut3+/- male but not female mice (5 months of age) displayed reduced CSF glucose/lactate concentrations with no change in brain Glut1, Mct2, glucose uptake or ATP. Exogenous insulin-induced hypoglycemia increased brain glucose uptake in glut3+/- males alone. Higher plasma-CSF ketones (β-hydroxybutyrate) and lower brain Glut3 in females vs males proved protective in the former while enhancing vulnerability in the latter. As a consequence, increased synaptic proteins (neuroligin4 and SAPAP1) with spontaneous excitatory postsynaptic activity subsequently reduced hippocampal glucose content and increased brain amyloid β1-40 deposition in an age-dependent manner in glut3+/- males but not females (4 to 24 months of age). We then explored the protective effect of a ketogenic diet on ultrasonic vocalization, sociability, spatial learning and memory, and electroencephalogram seizures in male mice (7 days to 6 to 8 months of age) alone. A ketogenic diet partially restored sociability without affecting perturbed vocalization, spatial learning and memory, and reduced seizure events. We conclude that (1) sex-specific and age-dependent perturbations underlie the phenotype of glut3+/- mice, and (2) a ketogenic diet ameliorates seizures caused by increased cortical excitation and improves sociability, but fails to rescue vocalization and cognitive deficits in glut3+/- male mice.

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Brain / metabolism*
  • Brain / physiopathology
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Diet, Ketogenic*
  • Electroencephalography
  • Female
  • Glucose / metabolism
  • Glucose Transporter Type 3 / genetics
  • Glucose Transporter Type 3 / metabolism*
  • Male
  • Memory / physiology
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Seizures / diet therapy*
  • Seizures / metabolism
  • Seizures / physiopathology
  • Sex Factors
  • Social Behavior*
  • Spatial Learning / physiology
  • Vocalization, Animal / physiology


  • Cell Adhesion Molecules, Neuronal
  • Glucose Transporter Type 3
  • Nerve Tissue Proteins
  • Nlgn4 protein, mouse
  • Glucose