While most children with FSE do

While most children with FSE do well (Verity et al., 1993; Shinnar et al., 2001), our findings in a rat model that mimics the clinical condition (Dube et al., 2006) raises the question of whether children who seemingly do well after febrile status epilepticus actually are spared injury or whether they compensate for the injury. To address this question clinically it will be necessary to do detailed neuropsychological and educational evaluations in children with FSE to determine if they learn differently from children without a history of seizures. If a different learning strategy is detected, learning how children compensate for the injury will be important in developing educational strategies for children with cognitive dysfunction following FSE. Neuronal oscillations, and presumably temporal coding, are malleable with over-training in rats (Kleen et al., 2011) and it is hoped that educational intervention in children would improve temporal coordination. While improving the temporal coordination of hippocampal purchase Mitiglinide Calcium in children is one way of attenuating cognitive deficits, an ideal treatment would be stop the cascade of events following FSE that result in these deficits. Our previous work has implied that the metabolic state of the whole brain, as well as the hippocampus and amygdala, in a 2-hour period post FSE can predict cognitive outcome in the active avoidance task (Barry et al., 2015). Therefore, it would be most interesting to see if improving metabolic regulation in the period following FSE would ultimately decrease the likelihood of learning and memory deficits and result in hippocampal networks with normal levels of temporal coordination. While exceedingly complex, there are several candidate physiological mechanisms that arise as a result of a cascade of events that follow FSE that could ultimately affect temporal coordination over the course of network development. Hyperthermia induced febrile seizures have been found to increase Ih current in hippocampal pyramidal cells, ultimately leading to cellular hyperexcitability (Chen et al., 1999, 2001; Dyhrfjeld-Johnsen et al., 2008). How changes in Ih current, or other FSE induced changes such as inflammatory cascades (Choy et al., 2014) affect the development of the hippocampal microcircuitry that underpins temporal coordination is not yet known. Apart from ion channel alterations, changes to the dendritic structure or number of synapses along the apical dendrites of CA1 cells may be altered following the FSE event. These changes can then dramatically alter the hippocampal network architecture, resulting in either FSE-NL or FSE-NL phenotypes. Alterations of pyramidal cell excitability or interneuron types such as basket cells, oriens-lacunosum moleculare cells (O-LM), or bistratified cells are likely candidates for disrupting temporal organization of the hippocampus. O-LM cells that partner with excitatory inputs from entorhinal cortex at the distal dendrites of CA1 cells while the excitatory input of CA3 cells is matched by the bistratified interneuron family at their inputs to CA1 at stratum radiatum. Finally, the basket family of interneurons fire rhythmic bursts in register with theta oscillations, thereby producing critical inhibitory currents in the region of the pyramidal cell bodies (Klausberger et al., 2003, 2004). More experimental work will be necessary to determine if and how alterations in these cell types following FSE might ultimately affect the microcircuitry of temporal coordination, as determined by the integration of CA1 cell activity with inputs from CA3 or the entorhinal cortex at theta frequency. We have described cognitive outcome and corresponding physiological changes as discrete conditions, adaptation and dysfunction. We took this tack primarily because the behavioral data we describe here and in our previous work (Barry et al., 2015) strongly indicated a bimodal outcome. FSE rats learn in a similar manner to controls (FSE-L) or they do not learn the task at all, even with generous amounts of extra training (FSE-NL). We credit the nature of the task for pointing to the physiological differences in FSE-L and FSE-NL animals that also appear to be bimodal, with either increased or decreased organization of CA1 place cell activity by theta. It is possible that another spatial task with a larger sample size may be able to find a continuum between alterations in physiology or levels of temporal coordination and performance.