• Glutamate;
  • γ-Aminobutyric acid;
  • Neuroenergetics;
  • Magnetic resonance spectroscopy;
  • Human;
  • Epilepsy;
  • Ketogenic diet

Summary: The application of magnetic resonance spectroscopy (MRS) to study brain glutamate and γ-aminobutyric acid (GABA) metabolism and the coupling of neurotransmitter cycling to neuroenergetics has provided several new, and controversial, insights into the relationship of brain metabolism and function in humans and animal models. Contrary to the previous view of separate metabolic and neurotransmitter pools of glutamate, the glutamate–glutamine cycle has been shown to be a major metabolic pathway tightly coupled to cerebral electrical activity and glucose metabolism. The glycogen-shunt model provides a mechanistic explanation for the uncoupling of glucose consumption and oxidation during enhanced cerebral electrical activity. A ketogenic diet improves the cerebral energy state of patients with refractory epilepsy. Ketones may act by providing oxidative fuel for non–neurotransmission-linked cerebral energy needs. This resulting sparing effect on glucose essentially provides an extra source of substrate to eliminate synaptic glutamate, which ultimately reduces excitability. Postictal glutamate reuptake is threefold slower in the gliotic yet epileptogenic human hippocampus, suggesting partial dysfunction of the glia, slowing the glutamate–glutamine cycle. Glutamate and GABA metabolism are coupled at the metabolic and functional levels. GABAergic neurons are dependent on glia to provide glutamine for GABA synthesis (GABA–glutamine cycle). Occipital GABA levels are below normal in many patients with refractory complex partial seizures and juvenile myoclonic epilepsy. Patients with lower GABA levels have slower rates of GABA synthesis. In the human visual cortex, GABA concentrations, and therefore rates of GABA synthesis, appear to be coupled to functional activity and inversely related to cortical excitability. Studies of glutamate/GABA/glutamine cycles, ketone body metabolism, and functional neuroenergetics should provide further insight into the metabolic mechanisms controlling cerebral excitability.