The antiepileptic and ictogenic effects of optogenetic neurostimulation of PV-expressing interneurons

J Neurophysiol. 2016 Oct 1;116(4):1694-1704. doi: 10.1152/jn.00744.2015. Epub 2016 Jul 13.


Parvalbumin (PV)-expressing interneurons exert powerful inhibitory effects on the normal cortical network; thus optogenetic activation of PV interneurons may also possess antiepileptic properties. To investigate this possibility we expressed channelrhodopsin 2 in PV interneurons by locally injecting the Cre-dependent viral vector AAV2/1-EF1a-DIO-ChETA-EYFP into the S1 barrel cortex of PV-Cre mice. Approximately 3-4 wk later recurrent electrographic seizures were evoked by local application of the chemoconvulsant 4-aminopyridine (4-AP); the ECoG and unit activity were monitored with extracellular silicone electrodes; and PV interneurons were activated optogenetically during the ictal and interictal phases. Five- to ten-second optogenetic activation of PV interneurons applied during electrographic seizures (ictal phase) terminated 33.7% of electrographic seizures compared with only 6% during sham stimulation, and the average electrographic seizure duration shortened by 38.7 ± 34.2% compared with sham stimulation. In contrast, interictal optogenetic activation of PV interneurons showed powerful and robust ictogenic effects. Approximately 60% of interictal optogenetic stimuli resulted in electrographic seizure initiation. Single-unit recordings revealed that presumptive PV-expressing interneurons markedly increased their firing during optogenetic stimulation, while many presumptive excitatory pyramidal neurons showed a biphasic response, with initial suppression of firing during the optogenetic pulse followed by a synchronized rebound increase in firing at the end of the laser pulse. Our findings indicated that ictal activation of PV-expressing interneurons possesses antiepileptic properties probably due to suppression of firing in pyramidal neurons during the laser pulse. However, in addition interictal activation of PV-expressing interneurons possesses powerful ictogenic properties, probably due to synchronized postinhibition rebound firing of pyramidal neurons.

Keywords: epilepsy; interneurons; neocortex; neurostimulation; optogenetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminopyridine
  • Action Potentials
  • Animals
  • Disease Models, Animal
  • Electrocorticography
  • Epilepsy / physiopathology*
  • Epilepsy / therapy*
  • Interneurons / physiology*
  • Mice
  • Microelectrodes
  • Optogenetics*
  • Parvalbumins / metabolism*
  • Pyramidal Cells / physiology
  • Seizures / physiopathology
  • Seizures / therapy
  • Somatosensory Cortex / physiopathology


  • Parvalbumins
  • 4-Aminopyridine