Chronic inhibition of brain glycolysis initiates epileptogenesis.
Metabolic abnormalities found in epileptogenic tissue provide considerable evidence of brain hypometabolism, while major risk factors for acquired epilepsy all share brain hypometabolism as one common outcome, suggesting that a breakdown of brain energy homeostasis may actually precede epileptogenesis. However, a causal link between deficient brain energy metabolism and epilepsy initiation has not been yet established. To address this issue we developed an in vivo model of chronic energy hypometabolism by daily intracerebroventricular (i.c.v.) injection of the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) and also investigated acute effects of 2-DG on the cellular level. In hippocampal slices, acute glycolysis inhibition by 2-DG (by about 35%) led to contrasting effects on the network: a downregulation of excitatory synaptic transmission together with a depolarization of neuronal resting potential and a decreased drive of inhibitory transmission. Therefore, the potential acute effect of 2-DG on network excitability depends on the balance between these opposing pre- and postsynaptic changes. In vivo, we found that chronic 2-DG i.c.v. application (estimated transient inhibition of brain glycolysis under 14%) for a period of 4 weeks induced epileptiform activity in initially healthy male rats. Our results suggest that chronic inhibition of brain energy metabolism, characteristics of the well-established risk factors of acquired epilepsy, and specifically a reduction in glucose utilization (typically observed in epileptic patients) can initiate epileptogenesis. © 2017 Wiley Periodicals, Inc.
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.
Evgeniya
E
Samokhina
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.|Aix Marseille Université, Inserm, INS UMR_S 1106, 13005, Marseille, France.
Irina
I
Popova
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.|Aix Marseille Université, Inserm, INS UMR_S 1106, 13005, Marseille, France.
Anton
A
Malkov
Aix Marseille Université, Inserm, INS UMR_S 1106, 13005, Marseille, France.
Anton I
AI
Ivanov
Neuronal Oscillations Lab, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Daniela
D
Papadia
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Moscow, Russia.
Alexander
A
Osypov
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.
Maxim
M
Molchanov
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia.
Svetlana
S
Paskevich
Neuronal Oscillations Lab, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
André
A
Fisahn
Neuronal Oscillations Lab, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Misha
M
Zilberter
Aix Marseille Université, Inserm, INS UMR_S 1106, 13005, Marseille, France.
Yuri
0000-0003-3481-1453
Y
Zilberter
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D003847:Deoxyglucose / Q000008:administration & dosage; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology*; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley
D003847:Deoxyglucose
2-deoxy-D-glucose; energy metabolism; epilepsy; glucose utilization; hippocampus