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Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?

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Abstract

Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K+ by astrocytes, thereby leading to increased extracellular K+ and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K+ homeostasis and increased susceptibility to seizures in epilepsy.

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Abbreviations

FBPase:

Fructose-1,6-bisphosphatase

GS:

Glutamine synthetase

GSK3:

Glycogen synthase kinase 3

LD:

Lafora disease

MSO:

L-methionine-SR-sulfoximine

NKA:

Na+-K+-activated adenosintrisphosphatase

NREM:

Non rapid eye movement

PC:

Pyruvate carboxylase

PEPCK:

Phosphoenolpyruvate carboxykinase

PGB:

Polyglucosan body

TCA:

Tricarboxylic acid

VIP:

Vasoactive intestinal peptide

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Acknowledgments

The author S.M. thanks the grant KL2 RR033182 from the National Insititute of Health (NIH) to the University of Minnesota Clinical and Translational Science Institute (CTSI) for support.

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Authors and Affiliations

  1. MARBILab, Museo storico della fisica e Centro di studi e ricerche “Enrico Fermi”, Rome, Italy

    Mauro DiNuzzo & Federico Giove

  2. Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, USA

    Silvia Mangia

  3. Dipartimento di Fisica, Sapienza Università di Roma, Rome, Italy

    Bruno Maraviglia & Federico Giove

  4. Fondazione Santa Lucia IRCCS, Rome, Italy

    Bruno Maraviglia

  5. Magnetic Resonance for Brain Investigation Laboratory, Fondazione Santa Lucia IRCCS, Via Ardeatina 306, 00179, Rome, Italy

    Mauro DiNuzzo

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  1. Mauro DiNuzzo
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  2. Silvia Mangia
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  3. Bruno Maraviglia
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  4. Federico Giove
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Correspondence to Mauro DiNuzzo.

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DiNuzzo, M., Mangia, S., Maraviglia, B. et al. Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?. Metab Brain Dis 30, 307–316 (2015). https://doi.org/10.1007/s11011-014-9524-5

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