AbstractA large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience a deficit in oxidative phosphorylation, and consequently in ATP, are frequently accompanied by severe seizures. This observation is paradoxical given that neuronal excitation imposes a high demand of ATP in neurons. The mechanisms underlying neuronal hyperexcitation in these pathologies remains unclear. Most of the ATP synthesized in neurons derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier. To address the question of how neurons can be hyperexcitable with reduced levels of ATP, we generated mice in which the mitochondrial pyruvate carrier was genetically inactivated in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation in these excitatory neurons, mice were normal at rest. In response to mild inhibition of GABA mediated synaptic activity they rapidly developed severe seizures and died, whereas under similar conditions the behaviour of control mice remained unchanged. We show that neurons with a deficient mitochondrial pyruvate carrier are intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduces M-type potassium channel activity. Provision of ketone bodies restores energy status, calcium homeostasis and M-channel activity and attenuates seizures in animals fed a ketogenic diet.One Sentence SummaryDecreased OXPHOS and Ca2+-mediated neuronal hyperexcitability lead to seizure in a mouse model of mitochondrial pyruvate import deficiency.
Acute changes in nerve excitability following oxaliplatin treatment in mice
