Original Article

Perinatal Immune Activation Produces Persistent Sleep Alterations and Epileptiform Activity in Male Mice

  • Neuropsychopharmacology volume 43, pages 482491 (2018)
  • doi:10.1038/npp.2017.243
  • Download Citation
Received:
Revised:
Accepted:
Published:

Abstract

Increasing evidence suggests a role for inflammation in neuropsychiatric conditions, including autism spectrum disorder (ASD). Previous work in rodents has established that immune activation during critical developmental periods can cause phenotypes that reproduce core features of ASD, including decreased social interaction, aberrant communication, and increased repetitive behavior. In humans, ASD is frequently associated with comorbid medical conditions including sleep disorders, motor hyperactivity, and seizures. Here we use a ‘two-hit’ immune-activation paradigm to determine whether perinatal immune activation can also produce these comorbid features in mice. In this paradigm, we treated timed-pregnant mice with polyinosinic:polycytidylic acid (Poly I:C), which simulates a viral infection, on gestational day 12.5 according to an established maternal immune activation regimen. A subset of the offspring also received a second ‘hit’ of lipopolysaccharide (LPS), which simulates a bacterial infection, on postnatal day 9. At 6 weeks of age, mice were implanted with wireless telemetry transmitters that enabled continuous measurements of electroencephalography (EEG), electromyography (EMG), locomotor activity, and subcutaneous temperature. Effects at 7 and 12 weeks of age were compared. Both prenatal Poly I:C and postnatal LPS produced changes in locomotor activity and temperature patterns, increases in slow-wave sleep, and shifts in EEG spectral power, several of which persisted at 12 weeks of age. Postnatal LPS also produced persistent increases in spontaneous bursts of epileptiform activity (spike-wave discharges) that occurred predominantly during sleep. Our findings demonstrate that early-life immune activation can lead to long-lasting physiologic perturbations that resemble medical comorbidities often seen in ASD and other neuropsychiatric conditions.

  • Subscribe to Neuropsychopharmacology for full access:

    $481

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. , , , , , (2017). Hyperactivity and male-specific sleep deficits in the 16p11.2 deletion mouse model of autism. Autism Res 10: 572–584.

  2. , , (2014). Toll-like receptors as developmental tools that regulate neurogenesis during development: an update. Front Neurosci 8: 272.

  3. , (2012). The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33: 267–286.

  4. , (2016). Epilepsy and autism. Cold Spring Harb Perspect Med 6: a022749.

  5. (2007). Epilepsy in autism spectrum disorders. Eur Child Adolesc Psychiatry 16: 61–66.

  6. , , , , , (2006). Frequency of epileptiform EEG abnormalities in a sequential screening of autistic patients with no known clinical epilepsy from 1996 to 2005. Epilepsy Behav 8: 267–271.

  7. (2017). Where does EEG come from and what does it mean? Trends Neurosci 40: 208–218.

  8. , , , , , et al (2017). Neonatal immune challenge with lipopolysaccharide triggers long-lasting sex- and age-related behavioral and immune/neurotrophic alterations in mice: relevance to autism spectrum disorders. Mol Neurobiol (e-pub ahead of print)..

  9. , (2015). Clinical characteristics of children and young adults with co-occurring autism spectrum disorder and epilepsy. Epilepsy Behav 47: 183–190.

  10. , , , , , et al (2009). Development of spike-wave seizures in C3H/HeJ mice. Epilepsy Res 85: 53–59.

  11. , (2016). Maternal immune activation: implications for neuropsychiatric disorders. Science 353: 772–777.

  12. , , (1999). Genetic determinants of sleep regulation in inbred mice. Sleep 22: 155–169.

  13. , , , , , et al (2008). Postnatal inflammation increases seizure susceptibility in adult rats. J Neurosci 28: 6904–6913.

  14. , , , , , et al (2014). Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun 5: 5748.

  15. , , , , , et al (2017). Prenatal fever and autism risk. Mol Psychiatry (e-pub ahead of print).

  16. , (2010). Shaping functional architecture by oscillatory alpha activity: gating by inhibition. Front Hum Neurosci 4: 186.

  17. (2011). The neurology of autism spectrum disorders. Curr Opin Neurol 24: 132–139.

  18. , , , , , et al (2016). Maternal infection during pregnancy and risk of autism spectrum disorders: a systematic review and meta-analysis. Brain Behav Immun 58: 165–172.

  19. , (2010). The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11: 373–384.

  20. (1971). Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823.

  21. (2008). The role of cytokines in sleep regulation. Curr Pharm Des 14: 3408–3416.

  22. , , (2011). Cytokines in immune function and sleep regulation. Handb Clin Neurol 98: 229–240.

  23. , , , , , (2014). Prevalence and neonatal factors associated with autism spectrum disorders in preterm infants. J Pediatr 164: 20–25.

  24. , , (2017). Behavioral methods to study anxiety in rodents. Dialogues Clin Neurosci 19: 181–191.

  25. , , , , (2015). Maternal immune activation in nonhuman primates alters social attention in juvenile offspring. Biol Psychiatry 77: 823–832.

  26. , , , , (2012). Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain Behav Immun 26: 607–616.

  27. , , , , , (2015). Cytokine aberrations in autism spectrum disorder: a systematic review and meta-analysis. Mol Psychiatry 20: 440–446.

  28. , , , , , et al (2015). Toward an immune-mediated subtype of autism spectrum disorder. Brain Res 1617: 72–92.

  29. , , (2017). the immunology of behavior-exploring the role of the immune system in brain health and illness. Neuropsychopharmacology 42: 1–4.

  30. , , , , , et al (2016). Altered behavior, sleep and epileptiform activity in a perinatal immune acivation mouse model of autism spectrum disorder (ASD). Neuropsychopharmacology 41: S474–S475.

  31. , , , , , (2004). Behavioral state instability in orexin knock-out mice. J Neurosci 24: 6291–6300.

  32. , , , , , et al (2014). Spike-wave discharges in adult Sprague-Dawley rats and their implications for animal models of temporal lobe epilepsy. Epilepsy Behav 32: 121–131.

  33. , (2009). Sleep problems in autism spectrum disorders: prevalence, nature, & possible biopsychosocial aetiologies. Sleep Med Rev 13: 403–411.

  34. , (2014). gamma-band abnormalities as markers of autism spectrum disorders. Biomark Med 8: 353–368.

  35. , , , , , (2006). Inflammation in preterm and term labour and delivery. Semin Fetal Neonatal Med 11: 317–326.

  36. , , , , , et al (2014). Estimates of possible severe bacterial infection in neonates in sub-Saharan Africa, south Asia, and Latin America for 2012: a systematic review and meta-analysis. Lancet Infect Dis 14: 731–741.

  37. , , , , (2013). Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 106-107: 1–16.

  38. , , , , (2008). The frequency of microbial invasion of the amniotic cavity and histologic chorioamnionitis in women at term with intact membranes in the presence or absence of labor. Am J Obstet Gynecol 199: 375 e371–375 e375.

  39. , , , , (2007). Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27: 10695–10702.

  40. , (2015). Autism and epilepsy: exploring the relationship using experimental models. Epilepsy Curr 15: 206–210.

  41. , , , (2017). Cntnap2 knockout rats and mice exhibit epileptiform activity and abnormal sleep-wake physiology. Sleep 40 (e-pub ahead of print).

  42. , , , , , (2013). Resting state EEG abnormalities in autism spectrum disorders. J Neurodev Disord 5: 24.

  43. , , , , , et al (2017). Effects of chronic social defeat stress on sleep and circadian rhythms are mitigated by kappa-opioid receptor antagonism. J Neurosci 0885–0817.

  44. , (2013). Sex differences in autism spectrum disorders. Curr Opin Neurol 26: 146–153.

  45. , , , , , et al (2015). Family history of autoimmune diseases is associated with an increased risk of autism in children: a systematic review and meta-analysis. Neurosci Biobehav Rev 55: 322–332.

  46. , , , , , et al (2013). Prenatal immune challenge in rats increases susceptibility to seizure-induced brain injury in adulthood. Brain Res 1519: 78–86.

Download references

Acknowledgements

We thank Vadim Bolshakov, Kwang-Soo Kim, Woori Kim, and Yan Li for insightful discussions on this line of research.

Author information

Affiliations

  1. Basic Neuroscience Division, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA

    • Galen Missig
    • , Emery L Mokler
    • , James O Robbins
    • , Abigail J Alexander
    •  & William A Carlezon Jr
  2. Lurie Center for Autism, Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Lexington, MA, USA

    • Christopher J McDougle

Authors

  1. Search for Galen Missig in:

  2. Search for Emery L Mokler in:

  3. Search for James O Robbins in:

  4. Search for Abigail J Alexander in:

  5. Search for Christopher J McDougle in:

  6. Search for William A Carlezon in:

Corresponding author

Correspondence to William A Carlezon Jr.

Supplementary information

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)