Deconstructing epileptic circuits in a mouse model of SLC6A1 syndrome

解构 SLC6A1 综合征小鼠模型中的癫痫回路

• 批准号: 10508480
• 负责人: Yuliya Voskobiynyk
• 金额: $ 6.76万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10508480
• 关键词: Astrocytes; Attention; Brain; Cell Nucleus; Cerebral cortex; Clinical Management; Cognitive; Data; Development; Developmental Delay Disorders; Dissection; Electroencephalography; Electrophysiology (science); Epilepsy; Functional disorder; GABA Transporter 1; GABA transporter; Generations; Genes; Genetic; Hippocampus (Brain); Human; In Vitro; Intellectual functioning disability; Location; Locomotion; Mediating; Modeling; Motor; Mus; Muscle Tonus; Mutant Strains Mice; Mutation; Names; Neurodevelopmental Disorder; Neurons; Outcome; Patients; Physiological Processes; Point Mutation; Property; Role; Seizures; Series; Sleep; Sleep disturbances; Slice; Structure; Synapses; Syndrome; Techniques; Testing; Thalamic structure; Therapeutic Effect; Time; Transgenic Mice; Traumatic Brain Injury; Variant; Work; autism spectrum disorder; disability; effective therapy; exome sequencing; experience; extracellular; gamma-Aminobutyric Acid; in vivo; mind control; motor deficit; mouse model; network dysfunction; novel; optogenetics; post stroke; postsynaptic; prevent; receptor; response; therapeutic target; tool; uptake

PROJECT SUMMARY & ABSTRACT The SLC6A1 gene has been recently implicated in a spectrum of neurodevelopmental disorders including epilepsy, autism, and intellectual and motor disability, collectively named SLC6A1 syndrome. SLC6A1 encodes the GABA transporter GAT1, but the cellular and circuit mechanisms by which SLC6A1 mutations cause SLC6A1 syndrome remain unknown, thus hampering the development of effective treatments. To fill this gap, I propose to dissect the mechanisms that cause epilepsy in a new mouse model carrying a human SLC6A1 mutation. My preliminary data show that Slc6a1 S295L/+ mutation leads to state-dependent seizures in thalamocortical circuits, disrupting sleep. Motivated by these findings, I will test the central hypothesis that thalamic circuits are key regulators of epileptic seizures associated with SLC6A1 syndrome. To test this hypothesis, I will determine the impact of S295L mutation on synaptic and intrinsic properties of thalamocortical neurons and thalamic circuit excitability in brain slices, and on thalamocortical function in vivo. I will also investigate whether thalamic targeting with optogenetic tools can treat epileptic seizures. The proposed work will harness in vitro and in vivo electrophysiological and optogenetic circuit dissection techniques. These results will elucidate our basic understanding of GAT1 dysfunction and assess how the subsequent increased tonic GABA current might impact the thalamocortical circuit in SLC6A1 syndrome. Ultimately, this work will help identify potential therapeutic targets to treat SLC6A1-related epilepsy.

项目概要和摘要 SLC 6A 1基因最近被认为与一系列神经发育障碍有关， 癫痫、自闭症、智力和运动障碍，统称为SLC 6A 1综合征。SLC 6A 1编码 GABA转运蛋白GAT 1，但SLC 6A 1突变导致SLC 6A 1的细胞和电路机制 综合征仍然未知，从而阻碍了有效治疗的发展。为了填补这一空白，我建议 在携带人类SLC 6A 1突变的新小鼠模型中剖析导致癫痫的机制。 我的初步数据显示，Slc 6a 1 S295 L/+突变导致癫痫患者的状态依赖性癫痫发作。 丘脑皮层回路扰乱睡眠基于这些发现，我将检验中心假设， 丘脑回路是与SLC 6A 1综合征相关的癫痫发作的关键调节器。为了验证这一 假设，我将确定S295 L突变对丘脑皮质突触和内在特性的影响， 神经元和丘脑回路兴奋性，以及在体丘脑皮质功能。我也会 研究利用光遗传学工具靶向丘脑是否可以治疗癫痫发作。 拟议的工作将利用体外和体内电生理和光遗传电路解剖 技术.这些结果将阐明我们对GAT 1功能障碍的基本理解，并评估GAT 1功能障碍是如何影响GAT 1功能的。 随后增加的紧张性GABA电流可能会影响SLC 6A 1综合征的丘脑皮质回路。 最终，这项工作将有助于确定治疗SLC 6A 1相关癫痫的潜在治疗靶点。