Astrocyte control of synaptic NMDA receptors contributes to the progressive development of temporal lobe epilepsy

Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17540-5. doi: 10.1073/pnas.1311967110. Epub 2013 Oct 7.


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.

Keywords: electroencephalography; glia-to-neuron signaling; hippocampus; interictal spikes; pilocarpine mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Astrocytes / metabolism*
  • Electroencephalography
  • Epilepsy, Temporal Lobe / chemically induced
  • Epilepsy, Temporal Lobe / metabolism
  • Epilepsy, Temporal Lobe / physiopathology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / physiology
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Male
  • Membrane Potentials / physiology
  • Mice
  • Mice, Transgenic
  • Patch-Clamp Techniques
  • Pilocarpine
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • SNARE Proteins / genetics
  • SNARE Proteins / metabolism
  • Synapses / drug effects
  • Synapses / metabolism
  • Synapses / physiology*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology
  • Time Factors


  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • SNARE Proteins
  • Pilocarpine
  • 2-Amino-5-phosphonovalerate