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

目前，超过一半的颞叶癫痫(TLE)患者被认为患有 尽管有现有的药物治疗，但仍能控制癫痫发作。开发改进版的主要障碍之一 癫痫的治疗是我们对其背后的精确的细胞和电路机制的认识不足 TLE。TLE中一个重要但尚未解决的问题涉及到过度和 兴奋性主细胞(PC)轴突起始段(AIS)动作电位的异常产生。 AIS的高度靶向性突触控制是由一种独特的、进化上保守的GABA能细胞类型提供的， 轴突细胞(AAC)。AAC是唯一与PC AIS形成突触联系的GABA能神经元， 将AAC置于调控动作电位传递的战略位置。然而，由于技术上的原因 局限性，我们对AAC的确切连接及其在体内的功能及其调控的知识 在正常和癫痫患者的海马体内仍然极其有限。我们的R01拨款(NS121106) 重点是利用最近的技术突破的组合来测试AAC中介的假设 慢性TLE大鼠海马CA1区PC放电抑制改变，AAC光发生改变 调制可有效控制癫痫发作，减少认知共病。虽然盛行的教条 AAC只支配PC AIS，我们最近的初步结果令人惊讶地表明 AAC也可能直接与小白蛋白(PV)中间神经元突触，从而调节它们的活动。其他内容 对我们的发现进行调查，将使我们对AAC如何发挥中枢作用的理解进一步细微差别 CA1中兴奋性网络和抑制性网络的控制器，因此是TLE网络的关键参与者 过度兴奋。在这个行政补充项目中，我们建议将体内最先进的技术结合起来 使用CA1PV INS专门探索AAC的解剖和功能连接的技术。同时， 我们将采用类似的方法来研究TLE小鼠是否表现出AAC连接异常增加 添加到pv INS或改变pv INS在CA1中的输出活性。总而言之，我们兰迪斯奖的目标与 行政补充将受益于我们的R01拨款定义功能的目标，并对此做出贡献。 AAC在TLE中的调节和治疗潜力，同时也扩大了指导受训人员的机会 先进的方法。总体而言，这个项目将对促进我们对关键技术的理解产生重大影响 慢性癫痫的电路控制机制及未来新型抗癫痫药物的开发 治疗策略。

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.