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Lack of Astrocytic Glycogen Alters Synaptic Plasticity but Not Seizure Susceptibility

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Abstract

Brain glycogen is mainly stored in astrocytes. However, recent studies both in vitro and in vivo indicate that glycogen also plays important roles in neurons. By conditional deletion of glycogen synthase (GYS1), we previously developed a mouse model entirely devoid of glycogen in the central nervous system (GYS1Nestin-KO). These mice displayed altered electrophysiological properties in the hippocampus and increased susceptibility to kainate-induced seizures. To understand which of these functions are related to astrocytic glycogen, in the present study, we generated a mouse model in which glycogen synthesis is eliminated specifically in astrocytes (GYS1Gfap-KO). Electrophysiological recordings of awake behaving mice revealed alterations in input/output curves and impaired long-term potentiation, similar, but to a lesser extent, to those obtained with GYS1Nestin-KO mice. Surprisingly, GYS1Gfap-KO mice displayed no change in susceptibility to kainate-induced seizures as determined by fEPSP recordings and video monitoring. These results confirm the importance of astrocytic glycogen in synaptic plasticity.

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Acknowledgments

We thank Anna Adrover, Emma Veza, and Anna Guitart for technical assistance, Neus Prats and Mònica Aguilera from the IRB Histopathology Facility, and Laura Alcaide, Vanessa Hernandez, María Sánchez Enciso, and José M. González Martín for their help in animal handling and care. We also thank Olga Varea for helpful advice and discussions. IRB Barcelona and IBEC are recipients of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).

Funding

This study was supported by grants from the MINECO (BFU2017-82375-R to AG and JMD-G, RTI2018-099773-B-I00 to JADR and AH, and BFU2017-84345-P to JD and JG), the CIBER de Diabetes y Enfermedades Metabólicas Asociadas (ISCIII, Ministerio de Ciencia e Innovación), and a grant from the National Institutes of Health (NIH NINDS P01NS097197) to JG. The project also received funding from “la Caixa” Foundation (ID 100010434) under the agreement LCF/PR/HR19/52160007 with JADR. MKB has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 754510.

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Authors and Affiliations

  1. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain

    Jordi Duran, M. Kathryn Brewer & Joan J. Guinovart

  2. Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029, Madrid, Spain

    Jordi Duran & Joan J. Guinovart

  3. Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain

    Arnau Hervera & Jose Antonio del Rio

  4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain

    Arnau Hervera & Jose Antonio del Rio

  5. Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028, Barcelona, Spain

    Arnau Hervera & Jose Antonio del Rio

  6. Institute of Neurosciences, University of Barcelona, 08028, Barcelona, Spain

    Arnau Hervera & Jose Antonio del Rio

  7. Division of Neurosciences, Pablo de Olavide University, Seville, Spain

    Agnès Gruart & José M. Delgado-García

  8. Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028, Barcelona, Spain

    Joan J. Guinovart

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  1. Jordi Duran
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Contributions

JD and JJG conceived the study. JD generated and maintained the GYS1Gfap-Cre line. JD and MKB collected brain tissues and performed biochemical and histological analyses. AG and JMD-G performed electrophysiological studies before and after single kainate injections. AH and JAR performed seizure video-monitoring with multiple kainate injections. All authors analyzed data and contributed to the writing of the manuscript.

Corresponding author

Correspondence to Jordi Duran.

Ethics declarations

All experiments were carried out following European Union (2010/63/EU) and Spanish (BOE 34/11370-421, 2013) regulations for the use of laboratory animals. In addition, all experimental protocols were approved by the Ethics Committee of the Pablo de Olavide University.

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The authors declare that they have no conflicts of interest.

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Duran, J., Brewer, M.K., Hervera, A. et al. Lack of Astrocytic Glycogen Alters Synaptic Plasticity but Not Seizure Susceptibility. Mol Neurobiol 57, 4657–4666 (2020). https://doi.org/10.1007/s12035-020-02055-5

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