Seizure disorders cause significant morbidity and mortality, and many cases are refractory to current medical management. Thus, improved treatments are needed. Therapeutic advances might be developed from a better understanding of the antiepileptic mechanisms of brain acidosis. It has long been known that low pH effectively inhibits seizures and reduces neuron excitability, but the molecular mechanisms underlying these effects are poorly understood. The recent identification of proton receptors in the brain may provide a molecular link between brain pH and seizures. It was recently found that one of these receptors, the acid sensing ion channel ASIC1a is required for acid-evoked currents in central neurons. And consistent with an inhibitory effect on seizures, preliminary data indicate overexpressing ASIC1a in mice attenuates seizures. In contrast, disrupting ASIC1a makes seizures worse. Together, these observations suggest the hypothesis that ASIC1a mediates the antiepileptic effects of central acidosis and reduces neuron excitability. To test this hypothesis three aims are planned.
The first aim will test whether ASIC1a mediates antiepileptic effects of CO2, which rapidly crosses the blood-brain barrier and lowers central pH. Wild-type mice, ASIC1a null mice, and ASIC1a overexpressing transgenic mice will be injected with a chemoconvulsant and the anti-epileptic effects of CO2 relative to air will be compared between genotypes. The results will provide an indication of whether the anti-epileptic properties of ASIC1a and CO2 are related.
The second aim will test whether ASIC1a mediates the antiepileptic effects of acid in brain slices where pH can be better controlled.
The third aim will test the effects of ASIC1a on acid inhibition of action potentials in cultured hippocampal neurons. Preliminary data suggest ASIC1a may inhibit action potentials, which may help explain how ASIC1a inhibits seizures in vivo. Together these experiments will provide important insight into the historically well established but poorly understood antiepileptic effects of acid. They will also lead to additional mechanistic studies to clarify in more depth how ASIC1a exerts its antiepileptic effects. Importantly, these studies may also suggest ASIC1a as a novel therapeutic target for inhibiting seizures in patients. Identifying novel and broad antiepileptic mechanisms may be especially beneficial to patients with refractory disease. Seizures disorders cause significant morbidity and mortality and are often refractory to medical management. Studying novel features of seizure inhibition may lead to treatments with alternative mechanisms of action. In this application we explore the seizure inhibiting effects of a poorly understood gene, acid-sensing ion channel 1a, and we test whether ASIC1a contributes to the well-established but poorly understood antiepileptic effects of brain acidosis. These studies have the potential to foster the development of Asic1a antagonists as a novel therapeutic approach to seizures. ? ? ?
| Tao, Hirotaka; Manak, J Robert; Sowers, Levi et al. (2011) Mutations in prickle orthologs cause seizures in flies, mice, and humans. Am J Hum Genet 88:138-49 |
| Ziemann, Adam E; Schnizler, Mikael K; Albert, Gregory W et al. (2008) Seizure termination by acidosis depends on ASIC1a. Nat Neurosci 11:816-22 |
