We hypothesized that in epileptic brains citric acid cycle intermediate levels may be deficient leading to hyperexcitability. Anaplerosis is the metabolic refilling of deficient metabolites. Our goal was to determine the anticonvulsant effects of feeding triheptanoin, the triglyceride of anaplerotic heptanoate. CF1 mice were fed 0-35% calories from triheptanoin. Body weights and dietary intake were similar in mice fed triheptanoin vs. standard diet. Triheptanoin feeding increased blood propionyl-carnitine levels, signifying its metabolism. 35%, but not 20%, triheptanoin delayed development of corneal kindled seizures. After pilocarpine-induced status epilepticus (SE), triheptanoin feeding increased the pentylenetetrazole tonic seizure threshold during the chronically epileptic stage. Mice in the chronically epileptic stage showed various changes in brain metabolite levels, including a reduction in malate. Triheptanoin feeding largely restored a reduction in propionyl-CoA levels and increased methylmalonyl-CoA levels in SE mice. In summary, triheptanoin was anticonvulsant in two chronic mouse models and increased levels of anaplerotic precursor metabolites in epileptic mouse brains. The mechanisms of triheptanoin's effects and its efficacy in humans suffering from epilepsy remain to be determined.

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SUMMARYPurpose: Kv4.2 subunits contribute to the poreforming region of channels that express a transient, A-type K + current (A-current) in hippocampal CA1 pyramidal cell dendrites. Here, the A-current plays an important role in signal processing and synaptic integration. Kv4.2 knockout mice show a near elimination of the A-current in area CA1 dendrites, producing increased excitability in this region. In these studies, we evaluated young adult Kv4.2 knockout mice for spontaneous seizures and the response to convulsant stimulation in the whole animal in vivo and in hippocampal slices in vitro. Methods: Electroencephalogram electrode-implanted Kv4.2 knockout and wild-type mice were observed for spontaneous behavioral and electrographic seizures. The latency to seizure and status epilepticus onset in Kv4.2 knockout and wild-type mice was assessed following intraperitoneal injection of kainate. Extracellular field potential recordings were performed in hippocampal slices from Kv4.2 knockout and wild-type mice following the bath application of bicuculline. Results: No spontaneous behavioral or electrographic seizures were observed in Kv4.2 knockout mice. Following kainate, Kv4.2 knockout mice demonstrated a decreased seizure and status epilepticus latency as well as increased mortality compared to wild-type littermates. The background strain modified the seizure susceptibility phenotype in Kv4.2 knockout mice. In response to bicuculline, slices from Kv4.2 knockout mice exhibited an increase in epileptiform bursting in area CA1 as compared to wild-type littermates. Discussion: These studies show that loss of Kv4.2 channels is associated with enhanced susceptibility to convulsant stimulation, supporting the concept that Kv4.2 deficiency may contribute to aberrant network excitability and regulate seizure threshold. KEY WORDS: A-type K channel, Channelopathies, Seizures, Status epilepticus, Mouse.Kv4.2 subunits compose the pore-forming channel that contributes to the transient, rapidly activating and inactivating outward K + current (A-current) in CA1 pyramidal cell dendrites (Kim et al., 2005;Chen et al., 2006). The A-current in this region regulates the back-propagating action potential and synaptic integration (Hoffman et al., 1997). Therefore, Kv4.2 channels are critical regulators of postsynaptic excitability, and aberrant function or loss of Kv4.2 channels is likely to facilitate hyperexcitability and potentially seizure initiation and propagation in the hippocampus.Alterations in the Kv4.2 channel have been demonstrated in animal models of epilepsy. A decrease in Kv4.2 mRNA levels was found in rat hippocampus following pentylenetetrazol-induced seizures 1741-1751, 2009 doi: 10.1111/j.1528-1167.2009.02086.x FULL-LENGTH ORIGINAL RESEARCH1741 hippocampal excitability and a decrease in seizure threshold, there was a marked decrease in the expression of Kv4.2 channel subunits (Castro et al., 2001). Furthermore, in a rodent model of limbic seizures induced by pilocarpine, there was a significant decrease in Kv4...

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