Perinatal Immune Activation Produces Persistent Sleep Alterations and Epileptiform Activity in Male Mice.
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 co-morbid medical conditions including sleep disorders, motor hyperactivity, and seizures.
Here we use a ‘two-hit’ immune-activation paradigm to determine if perinatal immune activation can also produce these co-morbid 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 co-morbidities often seen in ASD and other neuropsychiatric conditions.
Neuropsychopharmacology accepted article preview online, 06 October 2017. doi:10.1038/npp.2017.243.