Functional integration of inhibitory interneuron progenitors in the adult brain

描述(申请人提供)：抑制性中间神经元在调节皮质网络功能方面发挥重要作用，它们的丧失与许多神经和精神障碍有关。因此，移植抑制性神经前体细胞可能是一种有用的方法来恢复疾病大脑中的抑制缺陷。我们的实验室最近 在发育性癫痫模型中，证明了来自内侧神经节隆起的前体细胞可以迁移，分化为GABA能中间神经元，并抑制自发性癫痫发作。尽管最近在移植策略上取得了这些进展，但来自胚胎端脑其他区域的抑制性神经前体细胞亚型对现有宿主电路的影响仍然很大程度上尚不清楚，特别是在移植到成人大脑中后。在这项博士后研究计划中，我将确定来自尾神经节隆起的GABA前体细胞在移植到成年齿状回后如何改变抑制回路。提出了两个特定的目标，以确定：(1)移植到成年海马后产生的前体细胞迁移和GABA能亚型的表型，以及(2)这些新的中间神经元如何改变齿状回中现有的突触电路。电生理结果将与细胞、分子和解剖学特征相关联。这项研究将提供关于GABA能前体细胞移植到成人脑内后突触连接的详细信息。 公共卫生相关性：许多神经疾病涉及抑制性中间神经元的丧失，移植方法在受影响的大脑区域产生新的皮质中间神经元亚型可能是一种有用的治疗方法。我将确定胚胎抑制性神经前体细胞在移植到 成年的海马体。通过确定这些细胞形成的突触连接，我们将能够开发出皮质神经元间替代疗法的方法，以恢复人类患病大脑的正常功能。

DESCRIPTION (provided by applicant): Inhibitory interneurons perform important roles in regulating cortical network function, and their loss is associated with a number of neurological and psychiatric disorders. As such, transplantation of inhibitory neuronal progenitor cells might be a useful method to restore deficits in inhibition in the diseased brain. Our laboratory recently demonstrated that progenitor cells derived from the medial ganglionic eminence can migrate, differentiate into GABAergic interneurons, and suppress spontaneous seizures in a developmental epilepsy model. Despite these recent advances in transplantation strategies, the effect of inhibitory neural progenitor cell subtypes derived from other regions of the embryonic telencephalon on existing host circuitry remains largely unknown, especially after transplant into the adult brain. In this postdoctoral fellowship proposal, I will determine how GABA-progenitor cells derived from the caudal ganglionic eminence alter inhibitory circuitry after transplant into the adult dentate gyrus. Two specific aims are proposed, to determine: (1) progenitor cell migration and phenotypes of GABAergic subtypes generated after transplant into the adult hippocampus, and (2) how these new interneurons alter existing synaptic circuitry in the dentate gyrus. Electrophysiological results will be correlated with cellular, molecular, and anatomical characteristics. This study will provide detailed information about the synaptic connectivity of GABAergic progenitor cells after transplant into the adult brain. PUBLIC HEALTH RELEVANCE: A number of neurological disorders involve the loss of inhibitory interneurons, and a transplantation method to generate new cortical interneuron subtypes in affected brain regions might be a useful therapeutic approach. I will determine how embryonic inhibitory neural progenitor cells integrate into existing circuits after transplant into the adult hippocampus. By determining the synaptic connections formed by these cells, we will be able to develop methods for cortical interneuron replacement therapies to restore normal function in the human diseased brain.