Ketones prevent oxidative impairment of hippocampal synaptic integrity through K\textlessinf\textgreaterATP\textless/inf\textgreater channels

Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (K\textlessinf\textgreaterATP\textless/inf\textgreater) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of K\textlessinf\textgreaterATP\textless/inf\textgreater channel activation. Ketones dose-dependently reversed oxidative impairment of hippocampal synaptic integrity, neuronal viability, and bioenergetic capacity, and this action was mirrored by the K\textlessinf\textgreaterATP\textless/inf\textgreater channel activator diazoxide. Inhibition of K\textlessinf\textgreaterATP\textless/inf\textgreater channels reversed ketoneevoked hippocampal protection, and genetic ablation of the inwardly rectifying K\textlesssup\textgreater+\textless/sup\textgreater channel subunit Kir6.2, a critical component of K\textlessinf\textgreaterATP\textless/inf\textgreater channels, partially negated the synaptic protection afforded by ketones. This partial protection was completely reversed by co-application of the K\textlessinf\textgreaterATP\textless/inf\textgreater blocker, 5-hydoxydecanoate (5HD). We conclude that, under conditions of oxidative injury, ketones induce synaptic protection in part through activation of K\textlessinf\textgreaterATP\textless/inf\textgreater channels.