Epilepsy, regulation of brain energy metabolism and neurotransmission

Abstract

Seizures are the result of a sudden and temporary synchronization of neuronal activity, the reason for which is not clearly understood. Astrocytes participate in the control of neurotransmitter storage and neurotransmission efficacy. They provide fuel to neurons, which need a high level of energy to sustain normal and pathological neuronal activities, such as during epilepsy. Various genetic or induced animal models have been developed and used to study epileptogenic mechanisms. Methionine sulfoximine induces both seizures and the accumulation of brain glycogen, which might be considered as a putative energy store to neurons in various animals. Animals subjected to methionine sulfoximine develop seizures similar to the most striking form of human epilepsy, with a long pre-convulsive period of several hours, a long convulsive period during up to 48 hours and a post convulsive period during which they recover normal behavior. The accumulation of brain glycogen has been demonstrated in both the cortex and cerebellum as early as the pre-convulsive period, indicating that this accumulation is not a consequence of seizures. The accumulation results from an activation of gluconeogenesis specifically localized to astrocytes, both in vivo and in vitro. Both seizures and brain glycogen accumulation vary when using different inbred strains of mice. C57BL/6J is the most "resistant" strain to methionine sulfoximine, while CBA/J is the most "sensitive" one. The present review describes the data obtained on methionine sulfoximine dependent seizures and brain glycogen in the light of neurotransmission, highlighting the relevance of brain glycogen content in epilepsies.

Fig. (1)

Schematic representation of the glucose-lactate shuttle between neurons and astrocytes (adapted from Pellerin [119], and Cloix [144]). Gln: glutamine, GlyS: glycogen synthase, GP: glycogen phosphorylase, GS: glutamine synthetase, GLAST, GLT-1: Na⁺-glutamate co-transporter, Glu: glutamate, Lac: lactate, LDH5: Lactate dehydrogenase 5, MCT: monocarbohydrate transporter, NA: noradrenaline, Pyr: pyruvate, VIP: vasointestinal peptide.

Fig. (2)

Electron micrographs of sections made in the parietal cerebral cortex of mice after the administration of methionine sulfoximine. Swiss mice were intraperitoneally injected with 100 mg/kg of methionine sulfoximine (B) or with saline as control (A). After intracardiac perfusion of glutaraldehyde, the brain tissue were taken off, washed in buffered sucrose, post-fixed in osmium tetroxide, dehydrated in graded alcohol and propylene oxide, and embedded in Effapoxy. The sections were made and stained with uranyl acetate and lead citrate and then, examined in an electron microscope. In control, beta glycogen particles are rare. After methionine sulfoximine administration, glycogen as alpha and beta particles considerably increases. Gly: glycogen; magnification A and B: x 15000.

Fig. (3)

Effect of various doses of MSO, both in vivo (A, C) and in vitro (B) using two different strains of mice, C57BL/6J and CBA/J. A: Induction of seizures expressed as the percentage of convulsing mice as a function of MSO doses. B: Variation of glycogen determined in cultured astrocytes as a function of MSO doses. C: Variation of glycogen content of mice cortices sacrificed at either predetermined time T4 and T24) or at the onset of seizures (Seiz). Adapted from Bernard-Hélary et al. [151].