The Impact of Early-Life Seizures on the Maturation of Corticohippocampal Frequency Coordination

Abstract

Children who develop epilepsy early in life are at high risk for hippocampal-dependent learning and memory impairments. Evidence suggests that seizures in early life impact learning and memory by interfering with neural oscillations in the entorhinal cortex–hippocampal circuit, thereby altering coordination within and between these regions at specific frequencies. However, several questions remain about the initiation and duration of this circuit discoordination as a result of early-life seizures (ELS). It remains unknown whether circuit discoordination is ELS model specific, if these effects are detectable immediately after seizure and are permanent, or if they are altered over the course of development. We hypothesize that ELS impairs corticohippocampal synaptic signaling at specific CA1 and dentate gyrus (DG) dendritic compartments, that these impairments arise directly after seizure induction and endure into adulthood. We used high-density laminar silicon probes spanning the CA1 and DG somatodendritic axes to assess theta and gamma spectral properties, current source density (CSD), and phase–amplitude coupling (PAC) at multiple phase bandwidths in Control (CTL) rats or ELS rats that experienced recurrent flurothyl-induced seizures as pups. Rats were evaluated at two ages: juvenile (P23) and adult (>P90). ELS adults exhibited oscillation properties similar to juveniles, suggesting a process of post-ELS dysmaturation with age. PAC results revealed that across the DG somatodendritic axis, ELS adults and ELS juveniles both exhibited an absence of slow gamma coupling. In contrast, ELS juvenile CA1 slow gamma coupling was intact, but was abolished in ELS adults. These results suggest that while ELS effects in the DG were immediate and permanent, CA1 effects occurred over a longer timescale during development. Lastly, our data shows a timecourse for normal CA1 and DG synaptic input frequency coordination that is already in place in CTL juveniles at P23, correlating with the fraction of mature dendrites. The results demonstrate that PAC between theta and gamma oscillations can serve as a proxy for the efficacy of synaptic-dendritic processes underlying the coordination of local and distributed networks. We highlight a process of post-seizure dysmaturation, distinguishing between early ELS effects and their long-term developmental consequences within subfields of the corticohippocampal circuit.