Brief activation of GABAergic interneurons initiates the transition to ictal events through post-inhibitory rebound excitation

Neurobiol Dis. 2018 Jan;109(Pt A):102-116. doi: 10.1016/j.nbd.2017.10.007. Epub 2017 Oct 10.


Activation of γ-aminobutyric acid (GABAA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABAA receptor activation and ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like ("ictal") event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABAA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABAA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.

Keywords: 4-Aminopyridine; Channelrhodopsin-2; Cortex; GABA; Ictal events; Interictal events; Interneurons; Optogenetics; Seizures; VGAT-ChR2.

MeSH terms

  • 4-Aminopyridine / administration & dosage
  • Action Potentials
  • Animals
  • Disease Models, Animal
  • Epilepsy, Temporal Lobe / physiopathology
  • Female
  • GABA Agents / administration & dosage
  • GABA-A Receptor Antagonists / administration & dosage
  • GABAergic Neurons / physiology*
  • Humans
  • Interneurons / physiology*
  • Male
  • Mice, Inbred C57BL
  • Neocortex / physiopathology
  • Optogenetics
  • Pyramidal Cells / physiology
  • Receptors, GABA-A / physiology
  • Seizures / chemically induced
  • Seizures / physiopathology*
  • Somatosensory Cortex / physiopathology*
  • gamma-Aminobutyric Acid / administration & dosage
  • gamma-Aminobutyric Acid / physiology


  • GABA Agents
  • GABA-A Receptor Antagonists
  • Receptors, GABA-A
  • gamma-Aminobutyric Acid
  • 4-Aminopyridine