Neurological insults during development are associated with later impairments in learning and memory. Although remedial training can help restore cognitive function, the neural mechanisms of this recovery in memory systems are largely unknown. To examine this issue we measured electrophysiological oscillatory activity in the hippocampus (both CA3 and CA1) and prefrontal cortex of adult rats that had experienced repeated seizures in the first weeks of life, while they were remedially trained on a delayed-nonmatch-to-sample memory task. Seizure-exposed rats showed initial difficulties learning the task but performed similar to control rats after extra training. Whole-session analyses illustrated enhanced theta power in all three structures while seizure rats learned response tasks prior to the memory task. Whilst performing the memory task, dynamic oscillation patterns revealed that prefrontal cortex theta power was increased among seizure-exposed rats. This enhancement appeared after the first memory training steps using short delays and plateaued at the most difficult steps which included both short and long delays. Further, seizure rats showed enhanced CA1-prefrontal theta coherence in correct trials compared to incorrect trials when long delays were imposed, suggesting increased hippocampal-prefrontal synchrony for the task in this group when memory demand was high. Seizure-exposed rats also showed heightened gamma power and coherence among all three structures during the trials. Our results demonstrate the first evidence of hippocampal-prefrontal enhancements following seizures in early development. Dynamic compensatory changes in this network and interconnected circuits may underpin cognitive rehabilitation following other neurological insults to higher cognitive systems.

Early-life seizures (ELS) are associated with long-term behavioral disorders including autism and ADHD, suggesting that frontal lobe structures may be permanently affected. We tested whether ELS produce structural alterations in the prefrontal cortex (PFC) and impair PFC-mediated function using an operant task of behavioral flexibility in rats. Adult rats that had been exposed to 75 flurothyl seizures during postnatal days 1–10 showed decreased behavioral flexibility in the task compared to controls over multiple behavioral sessions, measured as a lever preference asymmetry (p<0.001) and a decreased efficiency of attaining food rewards (p<0.05). ELS rats also showed an increased thickness of the PFC (p<0.01), primarily attributed to layer V (p<0.01) with no differences in cell density. These structural changes correlated with lever preference behavioral impairments (p<0.05). This study demonstrates that the consequences of ELS extend to the PFC, which may help explain the high prevalence of comorbid behavioral disorders following ELS.

Dravet syndrome (DS) is a severe epileptic encephalopathy beginning in infancy in which children have difficult to control seizures and cognitive impairment. The majority of children with DS carry mutate,ons of the gene Scn1a, which codes for the alpha subunit of the type 1 voltage-gated sodium channel and is important for the function of interneurons. Interneurons have a critical role in the generation of brain rhythms involved in cognitive processing. We hypothesized that children with DS with Scn1a mutations would have abnormal oscillatory activity. To address this hypothesis, we used EEG power spectral analysis during the wakening to determine if frequency and power are altered in 23 EEGs from 12 children with DS compared to 18 age-matched controls. While there were few differences between the EEG power spectra in DS and controls in children under 2 years, in older children group differences were apparent. In DS children between 3-5 years there were significant decreases in percentage of alpha power compared to controls and in DS children over age 6 years there was a marked increase of theta and decrease of alpha compared to controls. Developmental status paralleled the power spectral analysis with an increasing likelihood of having severe cognitive problems with increasing age. These results demonstrate that Scn1a mutations result in an age-dependent alteration in oscillatory process. Such abnormalities in developmental progression of oscillations may play an important role in poor cognitive development in children with DS.

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