Sex differences in behavioral pathology induced by subconvulsive stimulation during early postnatal life are overcome by epileptic activity in the pre-juvenile weanling period.

Chronic subconvulsive activity in early life leads to sex-related autistic-like deficits in handling, object recognition, and social performance in pre-pubertal rats. Since autism and epilepsy are common neurodevelopmental disorders with high coincidence, we tested whether early-life chronic subconvulsive activity compared to convulsive activity alters handling, spatial memory, lateralization, coping strategy and the seizure threshold in a sex-dependent manner. A hypothesis is that convulsive seizures may alter sex differences induced by subconvulsive (SC) activity. Serial subconvulsive doses of kainic acid (KA) were administered postnatally (0.25-1 mg/kg) for 15 days to induce the chronic subconvulsive phenotype (SC group). Age-matched controls and a subset of SC pups were exposed to a convulsive dose of KA (KA and SC + KA groups; 7.5 mg/kg) or flurothyl vapors. In our open handling test, controls and the ASD groups escaped to a similar degree whereas after convulsive seizures, the pups exhibited freezing behavior; no escapes occurred. In the spontaneous alternating T-Maze control males and females entered the left arm with higher frequency. The SC males but not SC females entered left and right arms to a similar degree; alternation rates were reduced to chance revealing a sex difference. However, in KA and SC + KA groups, there was a sharp loss of spontaneous alternation rates. The rapid repetitive entries shifted to the right in both sexes possibly be due to hippocampal injury and changes in network activity induced by status epilepticus. In the forced swim test (FST), control and CS females were more active than corresponding males. After convulsions, immobility was reduced and vertical mobility was increased in SC and SC + KA males suggesting an elevated coping strategy compared to females. Onset and severity of KA induced status epilepticus was delayed in SC males and females possibly due to desensitization of KA receptors. Following flurothyl exposure, control males had faster onset of twitches and clonic seizures than control females which disappeared after the sub-convulsive pre-treatment. Data suggest that behavioral manifestations are more readily detectable between males and females when low levels of hyperexcitation are present chronically in early postnatal development but diminished after tonic-clonic convulsions persist. Therefore, therapeutic interventions may benefit patients if initiated upon the initial onset of sex-related autistic pathologies, particularly in males, which may reduce subsequent vulnerability to seizures.

Chronic subconvulsive activity during early postnatal life produces autistic behavior in the absence of neurotoxicity in the juvenile weanling period.

The diagnosis of autism spectrum disorder (ASD) varies from very mild to severe social and cognitive impairments. We hypothesized that epigenetic subconvulsive activity in early postnatal life may contribute to the development of autistic behavior in a sex-related manner. Low doses of kainic acid (KA) (25-100 µg) were administered to rat pups for 15 days beginning on postnatal (P) day 6 to chronically elevate neuronal activity. A battery of classical and novel behavioral tests was used, and sex differences were observed. Our novel open handling test revealed that ASD males nose poked more often and ASD females climbed and escaped more frequently with age. In the social interaction test, ASD males were less social than ASD females who were more anxious in handling and elevated plus maze (EPM) tasks. To evaluate group dynamics, sibling and non-sibling control and experimental animals explored 3 different shaped novel social environments. Control pups huddled quickly and more frequently in all environments whether they socialized with littermates or non-siblings compared to ASD groups. Non-sibling ASD pups were erratic and huddled in smaller groups. In the object recognition test, only ASD males spent less time with the novel object compared to control pups. Data suggest that chronic subconvulsive activity in early postnatal life leads to an ASD phenotype in the absence of cell death. Males were more susceptible to developing asocial behaviors and cognitive pathologies, whereas females were prone to higher levels of hyperactivity and anxiety, validating our postnatal ASD model apparent in the pre-juvenile period.