Mechanisms by which T-type calcium channels increase seizure susceptibility

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Significance -- Epilepsy affects about 2.5 million people in the United States. If not properly controlled by antiepileptic drugs, seizure disorders can lead to lower quality of life and loss of productivity. One class of epilepsy is called idiopathic generalized epilepsy (IGE), because the cause is not known (idiopathic) and the seizures can alter activity throughout the brain (generalized). Although this type of epilepsy can be inherited, there appear to be many genes involved (polygenic). Mutations in the gene, CACNA1H, which encodes the Cav3.2 channel, have been discovered in IGE patients. Approach -- This study will test the hypothesis that these epilepsy variants lead to a gain of function, either by altering Cav3.2 channel activity, or by altering its expression in neurons. Cav3.2 channels are a special class of calcium channel that can open near the resting membrane potential of neurons. This calcium entry can affect neurons in two important ways, one to depolarize the membrane and cause the neuron to fire sodium action potentials, and two, to increase calcium within the neuron, a 2nd messenger involved in the activation of many cellular processes such as dendritic arborization. Which of these roles is affected by epilepsy variants? To provide insights into this question, the present grant will address the following specific aims: [1] to establish the mechanisms by which Cav3.2 channels are trafficked in neurons; and [2] determine whether epilepsy variants of Cav3.2 increase dendritic arborization and whether this can be reversed by novel T-channel antagonists. The approaches used to address these important issues include molecular biology, cell biology, fluorescent microscopy, electrophysiology, and pharmacology. Impact -- These studies are likely to impact the field of neuroscience by uncovering novel roles of T- channels in dendritic arborization and neuronal excitability, and by validating novel antagonists. The studies will likely have a clinical impact: showing that T-channel antagonists reverse the effects of Cav3.2 variants on dendritic development, thereby providing the rationale for their early use to cure epilepsy.