ROLE OF NON-GLUCOSE SUBSTRATES IN SYNCHRONIZED HIPPOCAMPAL BURSTING
Abstract number :
2.114
Submission category :
Year :
2003
Submission ID :
3913
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Matthew Valley, Steve Kriegler, Carl E. Stafstrom Neurology, University of Wisconsin, Madison, WI
Hypotheses for the mechanism of action of the ketogenic diet (KD) include a direct or indirect effect of ketosis, enhancement of GABAergic inhibition, and effects of lipids on neuronal excitability. Clinical data suggest a correlation between the level of ketosis and seizure control. We tested an alternative hypothesis, that decreased carbohydrate (glucose) availability plays a role in reducing excitability. It is known that in situations of low glucose availability (including the KD), non-glucose substrates (lactate, pyruvate, [beta]-hydroxybutyrate) can substitute for glucose and maintain synaptic transmission.
We tested the effects of non-glucose substrate on high-potassium-induced bursting of hippocampal CA3 neurons. Hippocampal slices from juvenile rats (P27-35) were exposed to elevated K[sub]o[/sub]+ (7.5 mM) to produce interictal epileptiform bursts. Burst fequency was monitored in response to substitutions of alternative energy sources (lactate, pyruvate, [beta]-hydroxybutyrate) for glucose.
Baseline extracellular recordings in standard ACSF with 10 mM glucose plus elevated K[sub]o[/sub]+ showed frequent epileptiform bursts at a frequency of 29.5 [plusmn] 6.1 per min. Addition of lactate to that ACSF did not significantly alter burst frequency. Substitution of lactate (10 mM) or pyruvate (10 mM) for glucose reduced burst frequency up to 80%, while replacement of glucose by [beta]-hydroxybutyrate (10 mM) abolished epileptiform bursting. With each substitution (lac, pyr, BHB), synaptic transmission was maintained and the effect on epileptiform bursting was reversible. To determine if extracellular glucose must enter the neuron to support maximal epileptiform burst firing, glucose transport was blocked with cytochalasin B (50 [mu]M) in the presence of normal glucose (10 mM); epileptiform bursting was abolished under this condition.
Glucose is essential for maximal epileptiform burst firing of hippocampal CA3 neurons. Replacement of glucose by lactate, pyruvate, or [beta]-hydroxybutyrate reduces burst frequency but synaptic transmission is maintained. Glucose must enter neurons to facilitate epileptiform bursting. Therefore, the KD mechanism of action may partially involve reduction of the normal glucose substrate.
[Supported by: Parents Against Childhood Epilepsy and The Charlie Foundation.]