Temporal lobe epilepsy (TLE) accounts for approximately 60% of all epilepsies, yet it remains untreatable for many patients. TLE is thought to result from large-scale changes in the expression of genes that are important for neurons to function and communicate. MicroRNAs are small molecules that can quickly and flexibly regulate the expression of many genes at once, making them attractive drug targets for TLE treatment. We have identified one microRNA, miR-218, as a strong candidate for contributing to the development of TLE. TLE patients have significantly less miR-218 compared to healthy individuals, but whether reduced miR-218 leads to TLE or is a consequence of the disease is not known. Our preliminary data show that neurons that lack miR-218 are hyper-active and animals are more susceptible to seizures. This suggests a critical role for miR-218 in healthy brain function and compels a detailed look at how altered miR-218 levels might contribute to TLE. The tools and expertise in our laboratory allow us to investigate how the function of different neuron subtypes might be affected by reduced miR-218 levels and how these changes come together to affect brain function. In this proposal, we aim to determine how miR-218 misexpression contributes to TLE by I) investigating which aspects of neuronal function and communication are controlled by miR-218, and II) determining how the genes regulated by miR-218 result in the functional properties we uncover.