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Edited* by Tullio Pozzan, Foundation for Advanced Biomedical Research, Padua, Italy, and approved September 16, 2013 (received for review June 26, 2013)
Significance
Temporal lobe epilepsy (TLE) is a chronic brain disorder characterized by the occurrence of spontaneous recurrent seizures. Much of our knowledge of epilepsy is based on how neurons contribute to this disorder. Here we provide a view in which glial cells (astrocytes) contribute to the progressive development of TLE. We have combined a model of epilepsy that more closely mimics the complex features of seizures in epileptic patients, with astrocyte-specific molecular genetics to identify how astrocytes modulate the progressive development of TLE, including seizure occurrence, brain damage, and behavioral deficits. We provide evidence of the glial regulation of neuronal NMDA receptors in this process. This study identifies astrocytes as a potential therapeutic target for the treatment of epilepsy.
Abstract
Astrocytes modulate neuronal activity, synaptic transmission, and behavior by releasing chemical transmitters in a process termed gliotransmission. Whether this process impacts epilepsy in vivo is not known. We show that genetic impairment of transmitter release from astrocytes by the expression of a glial dominant-negative SNARE domain in mice reduced epileptiform activity in situ, delayed seizure onset after pilocarpine-induced status epilepticus, and attenuated subsequent progressive increase in seizure frequency in vivo. The reduced seizure frequency was accompanied by attenuation of hippocampal damage and behavioral deficits. As the delay in seizure onset and the reduced seizure frequency were mimicked by intracerebroventricular delivery of the NMDA receptor (NMDAR) antagonist d-(-)-2-amino-5-phosphonopentanoate in WT littermates and because dominant-negative SNARE expression leads to a hypofunction of synaptic NMDARs, we conclude that astrocytes modulate epileptogenesis, recurrent spontaneous seizures, and pathophysiological consequences of epilepsy through a pathway involving NMDARs.
Footnotes
- ↵1To whom correspondence should be addressed. E-mail: philip.haydon{at}tufts.edu.
Author contributions: J.C. and P.G.H. designed research; J.C., J.D., and D.J.H. performed research; J.C., J.D., and D.J.H. analyzed data; and J.C. and P.G.H. wrote the paper.
P.G.H. is president and cofounder of GliaCure, Inc.
↵*This Direct Submission article had a prearranged editor.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1311967110/-/DCSupplemental.
Astrocytic modulation of epilepsy
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- Neuroscience
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