Glycolysis and synaptic transmission
Synaptic transmission refers to the process where an action potential invades a pre-synaptic nerve terminal and neurotransmitters are released to activate neurotransmitter receptors on the post-synaptic cell. The whole process involves many steps, not all of which are known. Studies of the relationship between glycolysis and synaptic transmission have generally been done in brain slices from the hippocampus, very similar to the preparation I use to study epilepsy. The published literature on glycolysis and synaptic transmission has some contradictions that may be due to different species and methods of tissue preparation. Here I will describe published work in rat hippocampal slices that agree with my own observations.
The metabolism of glucose in cells generally requires two processes. The first biochemical pathway is glycolysis, where glucose is broken down to pyruvate in the cytoplasm of the cell. Pyruvate is transported in to the mitochondria where second biochemical process occurs. This process is called the Krebs cycle (as well as the citric acid cycle or TCA cycle) and pyruvate is broken down in to carbon dioxide and water, with the release of the majority of energy from the original glucose molecule. The published literature is in agreement that removing extracellular glucose will eventually cause synaptic transmission to fail, usually in less than 60 minutes. Similar drops in synaptic transmission are seen if glycolysis is blocked by chemicals that inhibit enzymes of the glycolytic pathway. In the presence of normal extracellular glucose, the glycolytic inhibitors 2-deoxyglucose and iodoacetate both will cause synaptic transmission to fail.
It is not surprising that inhibiting the pathway whereby a neuron gets most of it energy causes synaptic transmission to fail. The next question addressed was whether or not synaptic transmission could be maintained if glucose were replaced by another energy source for the Kreb’s cycle. Investigators generally used pyruvate, which enters the mitochondria for use in the Kreb’s cycle, and lactate, which is rapidly converted in to pyruvate. Supplying either one of these energy sources when glucose is removed or the enzymes of glycolysis chemically inhibited (by 2-DG or iodoacetate), synaptic transmission is maintained, at least at low frequencies of synaptic transmission. This is in contrast to my work on epileptiform bursting activity in hippocampal slices. Epileptiform bursting behavior is reduced be removal of glucose, or adding 2-DG or iodoacetate even when lactate or pyruvate is also added. My model of the Ketogenic diet predicts that inhibiting glycolysis does not effect normal low-frequency synaptic transmission, but may effect high-frequency synaptic transmission seen during epilepsy. This may account for the observation that the Ketogenic Diet does not have as many cognitive side effects as other anti-epileptic drugs.
Endogenous monocarboxylates sustain hippocampal synaptic function and morphological integrity during energy deprivation. Izumi Y, Benz AM, Katsuki H, Zorumski CF. J Neurosci. 1997 Dec 15;17(24):9448-57. [PDF]
Copyright 2011 Steve Kriegler
