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Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy

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Abstract

The hippocampus of patients with mesial temporal lobe epilepsy is often hardened and shrunken, a condition known as sclerosis. Magnetic resonance imaging reveals an increase in the T2-weighted signal, while diffusion weighted imaging shows a higher apparent diffusion coefficient in sclerotic hippocampi, indicating increased water content. As water transport appears to be coupled to K+ clearance and neuronal excitability [4], the molecular basis of the perturbed water homeostasis in the sclerotic hippocampus was explored. The expression of aquaporin-4 (AQP-4), the predominant water channel in the brain, was studied with quantitative real time PCR analysis, light microscopic immunohistochemistry and high-resolution immunogold labeling. A significant increase in AQP-4 was observed in sclerotic, but not in non-sclerotic, hippocampi obtained from patients with medically intractable temporal lobe epilepsy. This increase was positively correlated with an increase in the astrocyte marker glial fibrillary acidic protein. AQP-4 was localized to the plasma membranes of astrocytes including the perivascular end-feet. Gene expression associated with increased AQP-4 was evaluated by high throughput gene expression analysis using Affymetrix GeneChip U133A and related gene networks were investigated with Ingenuity Pathways Analysis. AQP-4 expression was associated with a decrease in expression of the dystrophin gene, a protein implicated in the anchoring of AQP-4 in perivascular endfeet. The decreased expression of dystrophin may indicate a loss of polarity in the distribution of AQP-4 in astrocytes. We conclude that the perturbed expression of AQP-4 and dystrophin may be one factor underlying the loss of ion and water homeostasis in the sclerotic hippocampus and hypothesize that the reported changes may contribute to the epileptogenic properties of the sclerotic tissue.

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Acknowledgements

We thank Ms. Ilona Kovacs for excellent technical assistance with the immunohistochemistry, Dr. Aiping Lin for assistance with biostatistics, Ms. Shiela Westman for assistance with microarray analysis, and Dr. Ognen Petroff for his very helpful discussions and critiques of earlier versions of this paper. This work was supported by NS048434.

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Authors and Affiliations

  1. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Tih Shih Lee

  2. Department of Neurosurgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520-8082, USA

    Tore Eid, Dennis D. Spencer & Nihal C. de Lanerolle

  3. Keck Biotechnology Center, Yale University School of Medicine, New Haven, Connecticut, USA

    Shrikant Mane

  4. Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA

    Jung H. Kim

  5. Center for Molecular Biology and Neuroscience and Department of Anatomy, University of Oslo, 0317, Oslo, Norway

    Ole Petter Ottersen

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  1. Tih Shih Lee
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  2. Tore Eid
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Correspondence to Nihal C. de Lanerolle.

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The first two authors contributed equally to this study.

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Lee, T.S., Eid, T., Mane, S. et al. Aquaporin-4 is increased in the sclerotic hippocampus in human temporal lobe epilepsy. Acta Neuropathol 108, 493–502 (2004). https://doi.org/10.1007/s00401-004-0910-7

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