Early life Oxytocin treatment Attenuates Seizure Susceptibility in Male, but not Female, Fmr1-KO Mice

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability, and is frequently accompanied by seizures. Early-life treatment with the hormone oxytocin (OXT) improves social behavior and cognitive function in rodent models of autism with intellectual disability, including FXS, but potential OXT treatment effects on seizure susceptibility have not been evaluated. Here we tested, in both sexes, if intranasal OXT (iOXT) or saline (iSAL) during the second postnatal week reduces audiogenic seizures (AGS) in the Fmr1-Knockout (KO) mouse model of FXS. OXT given daily from postnatal day (P) 7 to P13 significantly reduced the incidence and severity of AGS and the latency to seize in adult male Fmr1-KOs. Female KOs exhibited less severe seizures that were unaffected by treatment. Wild type mice did not exhibit AGS independent of treatment. To test if antiepileptic effects of iOXT are age-dependent, a separate cohort received iOXT daily from P30 to P36. Male KOs receiving later treatments exhibited robust seizures that were comparable between OXT- and SAL-treatment groups, suggesting that OXTs enduring antiepileptic effects are confined to early postnatal treatments. Tests of acute OXT effects in adulthood demonstrated an attenuation of male Fmr1-KO AGS at testing 30-60 min and 1 day post-treatment but these effects were not evident 15 days later. These findings reveal marked sex differences in the propensity for audiogenic seizures in Fmr1-KO mice and demonstrate that early-life OXT treatment mitigates seizure susceptibility in males FXS model mice.