Maternal immune activation promotes hippocampal kindling epileptogenesis in mice

Ann Neurol. 2013 Jul;74(1):11-9. doi: 10.1002/ana.23898. Epub 2013 Aug 6.


Objective: Maternal immune activation (MIA) triggered by infections has been identified as a cause of autism in offspring. Considering the involvement of perturbations in innate immunity in epilepsy, we examined whether MIA represents a risk factor for epilepsy as well. The role of specific MIA components interleukin (IL)-6 and IL-1β was also addressed.

Methods: MIA was induced in C57BL/6 mice by polyinosinic-polycytidylic acid (PIC) injected during embryonic days 12 to 16. Beginning from postnatal day 40, the propensity of the offspring to epilepsy was examined using hippocampal kindling; autismlike behavior was studied using the sociability test. The involvement of IL-6 and IL-1β in PIC-induced effects was studied by the coadministration of the cytokine antibodies with PIC, and by delivering recombinant cytokines in lieu of PIC.

Results: The offspring of PIC-exposed mice exhibited increased hippocampal excitability, accelerated kindling rate, prolonged increase of seizure susceptibility after kindling, and diminished sociability. Epileptic impairments were abolished by antibodies to IL-6 or IL-1β. Neither of the recombinant cytokines alone increased the propensity to seizures; however, when combined, they produced effects similar to those induced by PIC. PIC-induced behavioral deficits were abolished by IL-6 antibodies and were mimicked by recombinant IL-6; IL-1β was not involved.

Interpretation: In addition to confirming the previously established critical role of IL-6 in the development of autismlike behavior following MIA, the present study shows that concurrent involvement of IL-6 and IL-1β is required for priming the offspring for epilepsy. These data shed light on mechanisms of comorbidity between autism and epilepsy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies / administration & dosage
  • Body Temperature / drug effects
  • Epilepsy / drug therapy
  • Epilepsy / etiology*
  • Female
  • Hippocampus / drug effects
  • Hippocampus / pathology*
  • Interferon Inducers / toxicity
  • Interleukin-1beta / blood
  • Interleukin-1beta / immunology
  • Interleukin-6 / blood
  • Interleukin-6 / immunology
  • Kindling, Neurologic / drug effects
  • Kindling, Neurologic / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Poly I-C / toxicity
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / immunology*
  • Prenatal Exposure Delayed Effects / physiopathology*
  • Social Behavior


  • Antibodies
  • Interferon Inducers
  • Interleukin-1beta
  • Interleukin-6
  • Poly I-C