Brain Advance Access originally published online on November 21, 2006
Brain 2007 130(2):535-547; doi:10.1093/brain/awl317
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TGF-ß receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis
1 Institute of Neurophysiology, Charité University Medicine Berlin, Germany 2 Center of Anatomy, Charité University Medicine Berlin, Germany 3 Department of Integrative Biology, UC Berkeley Berkeley, CA, USA 4 Helen Wills Neuroscience Institute, UC Berkeley Berkeley, CA, USA 5 Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto Toronto, ON, Canada 6 Departments of Physiology and Neurosurgery, Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev Beer-Sheva, Israel
Correspondence to: Dr Alon Friedman, Departments of Physiology and Neurosurgery, Soroka University Medical Centre and Zlotowski Center for Neuroscience, Ben-Gurion University, Beer-Sheva 84105, Israel E-mail: alonf{at}bgu.ac.il
It has long been recognized that insults to the cerebral cortex, such as trauma, ischaemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the blood–brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the mechanisms underlying these processes are not known. In this study, we reveal a novel mechanism for epileptogenesis in the injured brain. We used focal neocortical, long-lasting BBB disruption or direct exposure to serum albumin in rats (51 and 13 animals, respectively, and 26 controls) as well as albumin exposure in brain slices in vitro. Most treated slices (72%, n = 189) displayed hypersynchronous propagating epileptiform field potentials when examined 5–49 days after treatment, but only 14% (n = 71) of control slices showed similar responses. We demonstrate that direct brain exposure to serum albumin is associated with albumin uptake into astrocytes, which is mediated by transforming growth factor ß receptors (TGF-ßRs). This uptake is followed by down regulation of inward-rectifying potassium (Kir 4.1) channels in astrocytes, resulting in reduced buffering of extracellular potassium. This, in turn, leads to activity-dependent increased accumulation of extracellular potassium, resulting in facilitated N-methyl-D-aspartate-receptor-mediated neuronal hyperexcitability and eventually epileptiform activity. Blocking TGF-ßR in vivo reduces the likelihood of epileptogenesis in albumin-exposed brains to 29.3% (n = 41 slices, P < 0.05). We propose that the above-described cascade of events following common brain insults leads to brain dysfunction and eventually epilepsy and suggest TGF-ßRs as a possible therapeutic target.
Key Words: astrocytes; blood–brain barrier; epileptogenesis; neocortex; transforming growth factor beta receptors
Abbreviations: ACSF, artificial CSF; BBB, blood–brain barrier; DOC, deoxycholic acid; FITC, fluorescein isothiocyanate; GFAP, glial fibrillary acidic protein; [K+]o, extracellular potassium concentration; NMDA, N-methyl-D-aspartate; TGF-ßRs, transforming growth factor ß receptors
Received June 8, 2006. Revised September 19, 2006. Accepted October 14, 2006.
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