In vivo ketogenic diet treatment attenuates pathologic sharp waves and high frequency oscillations in in vitro hippocampal slices from epileptic K v 1.1α knockout mice

Summary The ketogenic diet ( KD ) is an effective therapy for pediatric refractory epilepsies; however, whether the KD changes the pathologic network oscillations generated by an epileptic brain remains unknown. We have reported that hippocampal CA 3 regions of epileptic K v1.1α knockout ( KO ) mice generate pathologic sharp waves ( SPW s) and high‐frequency oscillations ( HFO s) that have higher incidence, longer duration, and fast ripples compared to wild‐type (WT). Synaptic activity of hyperexcitable KO mossy fibers significantly decreased CA 3 principal cell spike‐timing reliability, which contributed to this network pathology. In addition, we have demonstrated that the KD reduces seizures by 75% in KO mice. Here, we determined whether 10‐ to 14‐day in vivo KD treatment exerts disease‐modifying effects that alter the spontaneous SPW ‐ HFO complexes generated by the hippocampal CA 3 region of KO mice in vitro using extracellular multielectrode array recordings. We found that KD treatment significantly attenuated the pathologic features of KO SPW s and ripples and reduced the incidence of fast ripples. The KD also improved spike‐timing reliability of KO CA 3 principal cells, decreased mossy fiber excitability, increased mossy fiber‐ CA 3 paired‐pulse ratios, and reduced coupling of field excitatory postsynaptic potentials and population spikes in the CA 3 region. Collectively, these data indicate that KD treatment modulates CA 3‐generated pathologic oscillations by dampening hyperactive mossy fiber synapses. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .