Maternal immune activation promotes hippocampal kindling epileptogenesis in mice

Abstract

Objective Maternal immune activation (MIA) triggered by infections, has been identified as a cause of autism in the 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-6 and interleukin-1β was also addressed. Methods MIA was induced in C57BL/6 mice by polyinosinic–polycytidylic acid (PIC) injected during embryonic days 12–16. Beginning from postnatal day 40, the propensity of the offspring to epilepsy was examined using hippocampal kindling; autism-like behavior was studied using the sociability test. The involvement of interleukin-6 and interleukin-1β in PIC-induced effects was studied by the co-administration 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 interleukin-6 or interleukin-1β. Neither of the recombinant cytokines alone increased the propensity to seizures; however when combined, they produced effects similar to the ones induced by PIC. PIC- induced behavioral deficits were abolished by interleukin-6 antibodies and were mimicked by recombinant interleukin-6; interleukin-1β was not involved. Interpretation In addition to confirming previously established critical role of interleukin-6 in the development of autism-like behavior following MIA, the present study shows that concurrent involvement of interleukin-6 and interleukin-1β is required for priming the offspring for epilepsy. These data shed light on mechanisms of comorbidity between autism and epilepsy.

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

“…Instead, these models highlight that synaptic elimination and envelopment of degenerating terminals can be a neuron autonomous event. Furthermore, our interpretation is also in line with other studies using the prenatal poly(I:C) administration model showing that significant neuronal and behavioral abnormalities can occur in the absence of overt microglia abnormalities (Garay et al, 2013;Missault et al, 2914;Pineda et al, 2013;Willi et al, 2013). Additional investigations will therefore be 25 needed to identify the cellular and molecular processes underlying the emergence of hippocampal synaptic deficits following prenatal immune challenge.…”

Long-term pathological consequences of prenatal infection: beyond brain disorders

“…Enhanced microglia activation in brain parenchyma, along with increased central production of secreted inflammatory factors, is often taken as a sign of ongoing inflammation in the CNS (48). The possibility that prenatal infection leads to chronic signs of brain inflammation has been supported only by some studies in rats and mice (17,69), whereas other rodent studies failed to find evidence for such neuroinflammatory processes extending into neonatal or adult life (5,43,96,119,151,157).…”

“…Indeed, it appears that more marked postnatal inflammatory changes are seen following relatively severe forms of maternal immune challenge, such as chronic exposure to immune system-activating agents throughout the entire gestational period (17). In contrast, acute or subchronic prenatal exposure to immune system-activating stimuli in mice and rats appears to be largely devoid of systemic and central inflammatory effects persisting into the juvenile or adult period (5,43,96,119,151,157). The latter may not seem surprising because inflammation is typically counteracted by homeostatic processes that mount antiinflammatory and/or immunosuppressive responses upon the induction of inflammation (132), which, in turn, dampen and finally resolve the post-acute fetal inflammatory responses to maternal immune activation (91).…”

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

“…Behavioral testing was performed using the 3-chamber test [21], adapted by our laboratory [22], between 10:00 AM and 1:00 PM. The apparatus was a 60×40-cm Plexiglas box divided into 3 connected chambers (Noldus, Leesburg, VA, USA).…”

“…Social novelty (second phase) was expressed as social novelty index and was calculated using a similar formula: [t new conspecific/ t new conspecific + t old conspecific ] × 100-50. On the resulting scale, the sociability and social novelty span from +50 (full preference for the conspecific during phase 1 and new conspecific during phase 2) to 0 (social indifference) to -50 (complete avoidance of the conspecific during phase 1 and of new conspecific during phase 2) [22][23][24]. Repetitive behavior was analyzed by calculating cumulative time spent grooming during each of the phases of the test and in each of the chambers of the apparatus.…”