Abstracts

It is well known that oxidative stress disrupts normal synaptic transmission and contributes to cellular injury and hyperexcitability. Seizure activity is also known to increase oxidative neuronal damage, which in turn can impair long-term potentiation (LTP), a model of learning and memory. Recently, we have shown that ketone bodies (KB) strongly suppress hydrogen peroxide (H[sub]2[/sub]O[sub]2[/sub])-induced oxidative stress in neocortical neurons via activation of mitochondrial K[sub]ATP[/sub](mK[sub]ATP[/sub]) channels ([italic]Kim et al, 2005 Soc Neurosci Abstr[/italic]). In the present study, we asked whether KB and diazoxide (DZ, an activator of mK[sub]ATP[/sub] channels) can protect against oxidative impairment of LTP in rat hippocampus., Acute hippocampal slices were prepared from Wistar rats (3-5 weeks), and extracellular field recordings were made in CA1 in the presence of various substrates. Schaffer collaterals were stimulated to evoke population spikes (PS) in the stratum pyramidale, and the stratum radiatum was stimulated using a theta-burst protocol (5 trains delivered at 0.2 Hz; each train consisting of five simulations, 0.1 ms, 100 Hz) to induce long-term potentiation (LTP)., H[sub]2[/sub]O[sub]2 [/sub](2 mM, 15 min application alone) strongly inhibited the field population spike (PS) by over 80%. Pretreatment of KB (acetoacetate and D-[beta]-hydrobutyrate, 1 mM each) or DZ (100 [mu]M) for 10 min prior to H[sub]2[/sub]O[sub]2[/sub] administration resulted in only a slight depression of PS amplitude (18% and 10%, respectively). The protective effects of KB and DZ were dose-dependent, and were completely reversed by 5-hydroxydecanoate (200 [mu]M; 5-HD, a mitoK[sub]ATP[/sub] blocker). In additional experiments, H[sub]2[/sub]O[sub]2[/sub] (200 [mu][Mu]) strongly suppressed LTP induction and maintenance. Neither KB (3 mM alone or applied as a 1:1 cocktail) nor DZ exerted any significant effects on TBS-induced LTP. However, co-application of KB or DZ completely prevented H[sub]2[/sub]O[sub]2-[/sub]induced impairment of LTP. On the other hand, pre-treatment with 5-HD reversed the protective effects of KB and DZ., Our findings suggest that KB can restore oxidative stress-induced impairment of normal synaptic transmission in the CA1 region of the hippocampus. Furthermore, the underlying neuroprotective mechanisms may involve modulation of mitochondrial K[sub]ATP[/sub] channels., (Supported by NIH grant NS 044846 (JMR) and the Barrow Neurological Foundation.)