Asynchronous GABA Release Is a Key Determinant of Tonic Inhibition and Controls Neuronal Excitability: A Study in the Synapsin II-/- Mouse

Cereb Cortex. 2015 Oct;25(10):3356-68. doi: 10.1093/cercor/bhu141. Epub 2014 Jun 24.


Idiopathic epilepsies have frequently been linked to mutations in voltage-gated channels (channelopathies); recently, mutations in several genes encoding presynaptic proteins have been shown to cause epilepsy in humans and mice, indicating that epilepsy can also be considered a synaptopathy. However, the functional mechanisms by which presynaptic dysfunctions lead to hyperexcitability and seizures are not well understood. We show that deletion of synapsin II (Syn II), a presynaptic protein contributing to epilepsy predisposition in humans, leads to a loss of tonic inhibition in mouse hippocampal slices due to a dramatic decrease in presynaptic asynchronous GABA release. We also show that the asynchronous GABA release reduces postsynaptic cell firing, and the parallel impairment of asynchronous GABA release and tonic inhibition results in an increased excitability at both single-neuron and network levels. Restoring tonic inhibition with THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol; gaboxadol), a selective agonist of δ subunit-containing GABAA receptors, fully rescues the SynII(-/-) epileptic phenotype both ex vivo and in vivo. The results demonstrate a causal relationship between the dynamics of GABA release and the generation of tonic inhibition, and identify a novel mechanism of epileptogenesis generated by dysfunctions in the dynamics of release that can be effectively targeted by novel antiepileptic strategies.

Keywords: GABA; asynchronous; epilepsy; synapsin; tonic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Excitatory Postsynaptic Potentials
  • GABA Agonists / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / physiology*
  • Hippocampus / physiopathology
  • Inhibitory Postsynaptic Potentials
  • Isoxazoles / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neural Inhibition*
  • Neurons / drug effects
  • Neurons / physiology*
  • Seizures / physiopathology
  • Synapsins / genetics
  • Synapsins / physiology*
  • gamma-Aminobutyric Acid / physiology*


  • GABA Agonists
  • Isoxazoles
  • Synapsins
  • gamma-Aminobutyric Acid
  • gaboxadol