Cytokine-dependent bidirectional connection between impaired social behavior and susceptibility to seizures associated with maternal immune activation in mice

Epilepsy Behav. 2015 Sep;50:40-5. doi: 10.1016/j.yebeh.2015.05.040. Epub 2015 Jun 21.


Maternal immune activation (MIA) results in the development of autism in the offspring via hyperactivation of IL-6 signaling. Furthermore, experimental studies showed that the MIA-associated activation of interleukin-1β (IL-1β) concurrently with IL-6 increases the rate and the severity of hippocampal kindling in mice, thus, offering an explanation for autism-epilepsy comorbidity. We examined whether epileptic phenotype triggered by prenatal exposure to IL-6 and IL-1β combination is restricted to kindling or whether it is reproducible in another model of epilepsy, whereby spontaneous seizures develop following kainic acid (KA)-induced status epilepticus. We also examined whether in mice prenatally exposed to IL-6 and IL-6+IL-1β, the presence of spontaneous seizures would exacerbate autism-like features. Between days 12 and 16 of pregnancy, C57BL/6J mice received daily injections of IL-6, IL-1β, or IL-6+IL-1β combination. At postnatal day 40, male offspring were examined for the presence of social behavioral deficit, and status epilepticus was induced by intrahippocampal KA injection. After 6weeks of monitoring for spontaneous seizures, sociability was tested again. Both IL-6 and IL-6+IL-1β offspring presented with social behavioral deficit. Prenatal exposure to IL-6 alleviated, while such exposure to IL-6+IL-1β exacerbated, the severity of KA-induced epilepsy. Increased severity of epilepsy in the IL-6+IL-1β mice correlated with the improvement of autism-like behavior. We conclude that complex and not necessarily agonistic relationships exist between epileptic and autism-like phenotypes in an animal model of MIA coupled with KA-induced epilepsy and that the nature of these relationships depends on components of MIA involved.

Keywords: Autism; Comorbidity; Cytokines; Epilepsy; Interleukin-1β; Interleukin-6; Maternal immune activation.

Publication types

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

MeSH terms

  • Animals
  • Autistic Disorder / physiopathology*
  • Cytokines / metabolism
  • Cytokines / physiology*
  • Disease Models, Animal
  • Disease Susceptibility / physiopathology
  • Epilepsy / chemically induced
  • Epilepsy / physiopathology*
  • Female
  • Hippocampus / metabolism
  • Interleukin-1beta / physiology
  • Interleukin-6 / physiology
  • Kainic Acid / adverse effects
  • Kindling, Neurologic / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Seizures / chemically induced
  • Status Epilepticus / physiopathology


  • Cytokines
  • Interleukin-1beta
  • Interleukin-6
  • Kainic Acid