Grant: Project Grant

Epilepsy, a brain disorder characterized by recurrent seizures, imposes significant challenges for individuals and society. Many individuals with epilepsy exhibit "pharmacoresistance"; that is, seizures that fail to respond to medication. Revealing the causal neurobiology underlying epilepsy - for example, neuron types and molecules that drive seizures - will likely prove critical for identifying next-generation for targets and treatments to overcome this pharmacoresistance. In our specialized collaboration spanning researchers in experimental neuroscience, along with clinicians involved in epilepsy neurosurgery and neuropathology, we seek to develop this knowledge on neurons and molecules that cause seizures. Through this collaboration, we have discovered an atypical neuron type, present in both the mouse and human brain, which may act as a seizure "detonator" due to its heightened excitability and extensive long-range connections. We will study this neuron type using a complement of experiments in mice, as well as living human brain tissue obtained from informed, consenting participants undergoing brain surgery for epilepsy. To begin, in epileptic mice, we will measure the ability of detonator neurons to drive widespread neural activity and seizures. In living human brain tissue, we will assess whether detonator neurons are similarly capable of driving widespread neural activity in the human brain. Using cutting-edge spatial transcriptomics experiments in both mice and humans, we will identify druggable molecules in detonator neurons and other cell types, and use this knowledge to disrupt these molecules using novel drug and genetic interventions. In the long term, these results may inform and guide the generation of new therapeutic approaches for epilepsy that was previously deemed pharmacoresistant.