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Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression

Molecular Psychiatry volume 18, pages 582–594 (2013)Cite this article

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Abstract

Depression is usually associated with alterations in the monoaminergic system. However, new evidences suggest the involvement of the glutamatergic system in the aetiology of depression. Here we explored the glutamatergic system in a rat model of depression (i.e., the flinders sensitive line (FSL)) to reveal the mechanism underlying the emotional and cognitive aspects associated with the disease. We showed a dramatically elevated level of baseline glutamatergic synaptic transmission by whole-cell recordings as well as impairment in long-term potentiation induced by high-frequency stimulation in hippocampal slices from FSL rats compared with Sprague–Dawley rats. At behavioural level, FSL rats displayed recognition memory impairment in the novel object recognition test. Enantioselective chromatography analysis revealed lower levels of D-serine in the hippocampus of FSL rats and both synaptic plasticity and memory impairments were restored by administration of D-serine. We also observed dysfunctional astrocytic glutamate regulation including downregulation of the glia glutamate transporter GLAST as shown by western blot. One possibility is that the dysfunctional astrocytic glutamate reuptake triggers a succession of events, including the reduction of D-serine production as a safety mechanism to avoid NMDA receptor overactivation, which in turn causes the synaptic plasticity and memory impairments observed. These findings open up new brain targets for the development of more potent and efficient antidepressant drugs.

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Acknowledgements

We thank Margareta Widing for technical assistance in the biochemical experiments, Carina DeRijck and Line Thierry for technical assistance in the HPLC experiments and Arash Hellysaz and Christian Broberger for assistance with the Neurolucida tracing. We also thank Gilad Silberberg and members of the Lindskog group for critically reading the manuscript. This work was supported by the Swedish Research Council and The Foundation for Strategic Research (ML) and the Wenner-Gren Foundation (MGG).

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Authors and Affiliations

  1. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden

    M Gómez-Galán, D De Bundel & M Lindskog

  2. Department of Pharmaceutical Chemistry and Drug Analysis, Centre for Neuroscience, Vrije Universiteit Brussel, Brussels, Belgium

    A Van Eeckhaut & I Smolders

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  1. M Gómez-Galán
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Correspondence to M Lindskog.

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Gómez-Galán, M., De Bundel, D., Van Eeckhaut, A. et al. Dysfunctional astrocytic regulation of glutamate transmission in a rat model of depression. Mol Psychiatry 18, 582–594 (2013). https://doi.org/10.1038/mp.2012.10

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  • DOI: https://doi.org/10.1038/mp.2012.10

Keywords

  • D-serine
  • FSL
  • GLAST
  • memory
  • mGluR2/3
  • synaptic plasticity

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