Effects of early-life seizures on coordination of hippocampal-prefrontal networks: influence of sex and dynamic brain states

The development and maturation of neurological circuits associated with learning and memory can be negatively impacted by early life seizures (ELS). While this has been a long-established concept, the pathophysiological mechanism underpinning ELS induced cognitive deficits is not as well understood. Further, the influences of crucial variables such as sex on cognitive outcomes following ELS have not been explored. We hypothesized that when compared to their control (CTL) counterparts, ELS rats would display impairments in spatial cognition as the result of impaired dynamic coordination between the hippocampus and medial prefrontal cortex (mPFC). To test this, flurothyl seizures were induced in both male and female rats at postnatal day (P) 15. We then assessed spatial cognition of the animals as adults using an active avoidance task. After initial testing, the animals were implanted with microwire tetrodes in the mPFC and CA1 of the hippocampus so that single cells and local field potentials could be recorded and analyzed during subsequent active avoidance testing and during sleep. We found that ELS male animals exhibited impairments in the active avoidance task learning while ELS female animals were unaffected. Control female rats had an increased mPFC-hippocampus coherence compared to control males across all bandwidths during active avoidance. ELS males that did not learn the task during training showed significantly lower coherences in all bandwidths than all other groups. ELS male non-learners also showed decreased dynamic coherence and cell modulation specifically in the 8–9 Hz range. Additionally, recordings taking during sleep showed that ELS male non-learners had less coherence and phase locking compared to all other groups. In male animals, ELS decreased hippocampus-mPFC coherence during active cognition and slow wave sleep while female rats showed no differences in these measures. The ELS animals that exhibited the lowest dynamic coherence were also the animals that performed the worst while learning the active avoidance task. Taken in concert, these results show that there may be a gender dependent influence on the effect of critical period seizures on spatial cognition. Furthermore, incoherent theta signal coordination between the mPFC and hippocampus presents a mechanism for adverse cognitive outcomes following ELS.