2023 NINDS Landis Mentorship Award - Administrative Supplement to NS121106 Control of Axon Initial Segment in Epilepsy

目前认为，颞叶癫痫（TLE）患者中有一半以上缺乏适当的治疗

Over half of all people with temporal lobe epilepsy (TLE) are currently believed to suffer from inadequately controlled seizures despite existing pharmacotherapies. One of the main obstacles to developing improved epilepsy therapies is our insufficient understanding of the precise cellular and circuit mechanisms underlying TLE. An important, but unresolved, question in TLE concerns the mechanisms underlying the excessive and dysregulated production of action potentials at the axon initial segment (AIS) of excitatory principal cells (PCs). Highly targeted synaptic control of the AIS is provided by a unique, evolutionarily conserved GABAergic cell type, the axo-axonic cell (AAC). AACs are the only GABAergic neuron that forms synaptic contacts with the PC AIS, placing AACs in a strategic position to regulate action potential transmission. However, due to technical limitations, our knowledge of the exact connectivity of AACs and their in vivo function, along with their regulation within the normal and epileptic hippocampus has remained extremely limited. Our R01 grant (NS121106) focuses on leveraging a combination of recent technical breakthroughs to test the hypothesis that AAC-mediated inhibition of PC discharges in hippocampal area CA1 is altered in chronic TLE in vivo, and that AAC optogenetic modulation may exert effective seizure control and decrease cognitive comorbidities. While the prevailing dogma has been that AACs exclusively innervate the PC AIS, our recent preliminary results surprisingly suggest that AACs may also directly synapse on parvalbumin (PV) interneurons and thus regulate their activity. Additional investigation into our finding would bring further nuance to our understanding of how AACs act as a central controller of both excitatory and inhibitory network in CA1, and thus as key players responsible for TLE network hyperexcitability. In this administrative supplement project, we propose to combine state-of-the-art in vivo techniques to specifically probe the anatomical and functional connectivity of AACs with CA1 PV INs. In parallel, we will perform similar approaches to study whether TLE mice show increased aberrant connectivity of AACs onto PV INs or altered PV INs output activity in CA1. Together, the aims in our Landis award-related administrative supplement will both benefit from and contribute to our R01 grant’s goal to define the function, regulation and therapeutic potential of AACs in TLE, while also expanding opportunities to mentor trainees in advanced approaches. Overall, this project will have a significant impact in advancing our understanding of key circuit control mechanisms in chronic epilepsy and will aid in the future development of novel antiseizure treatment strategies.