Abstracts

Rationale: Maternal immune activation (MIA) has been identified as a risk factor for autism in the offspring, with Interleukin-6 (IL-6) being a MIA component solely liable for the development of autism-associated behavioral and neuropathological abnormalities. Furthermore, experimental studies in mice showed that MIA increases the rate and the severity of hippocampal kindling in the offspring via concurrent activation of IL-6 and Interleukin-1β (IL-1β). The latter finding is congruent with a known comorbidity between autism and epilepsy. We examined whether such co-occurrence between autism-like and epileptic features in the MIA offspring is observed in another model of epilepsy, whereby spontaneous recurrent seizures develop following intrahippocampal infusion of kainic acid (KA). Methods: Between embryonic days 12 and 16 (E12-E16), C57BL/6 mice received daily intraperitoneal injections of IL-6, IL-1β, or their combination. At postnatal day 40 (P40) the offspring received single intrahippocampal injection of KA. Treatment regimens and sample sizes are in Table 1. Beginning from four weeks after KA injection, animals were monitored for spontaneous seizures for two weeks, and underwent the three-chamber sociability test to examine autism-like behavior. Results: Spontaneous seizures. None of KA-free animals exhibited spontaneous seizures. In the IL-6 offspring injected with KA, the number of recurrent seizures was significantly lower than in mice which received KA alone (11.5±5.8 vs. 2.8±1.7 respectively, p<0.05). Prenatal exposure to IL-1β had no effect of the spontaneous seizure count (13.4±8.3, p>0.05). In the IL-6+IL-1β offspring, there was a trend towards the increase of the number of seizures (27.8±10.85, p>0.05). Sociability. Diminished sociability was detected in the IL-6 and IL-6±IL-1β offspring (sociability index, SI -4.1±2.1 and 3.2±1.9 respectively, vs. 26.04±2.1 in naïve mice, p<0.05). In the absence of prenatal cytokine treatment, KA did not affect performance in the sociability test (SI 26.1±5.4, p>0.05). Impaired sociability was still observed in the IL-6 offspring injected with KA (SI 5.2±3.7, p<0.05 vs. naïve). In the IL-6±IL-1β offspring which received KA, SI was in normal range (27.7±3.05, p>0.05 vs. control, p<0.05 vs. IL-6+IL-1β, no KA). IL-1β offspring showed normal social behavior both without and with postnatal KA treatment. Conclusions: Surprisingly, the experiments showed that autism-like phenotype in the IL-6 offspring correlated with the reduced number of KA-induced spontaneous recurrent seizures, and at the same time relative increase of the severity of chronic epilepsy in the IL-6+IL-1β offspring correlated with the normalization of social behavior. Thus, under conditions of intrahippocampal KA model, there is apparent antagonism, rather than comorbidity between autism-like and epileptic features. The observations emphasize the complexity of mechanisms underlying autism-epilepsy connection, but also the importance of choosing proper experimental paradigms for examining said comorbidity. Supported by UCLA Today's and Tomorrow's Children Fund.