The role of TGF-ß2 in the KCC2-dependent maturation of GABAergic neurotransmission

TGF-α2 在 KCC2 依赖性 GABA 神经传递成熟中的作用

• 批准号: 217935450
• 负责人: Professorin Dr. Kerstin Krieglstein
• 金额: --
• 依托单位: Anatomie II: Abteilung für Molekulare Embryologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/217935450?language=en
• 关键词: role; TGF; KCC2; dependent; maturation

TGF-ßs are multifunctional extracellular signaling molecules, acting in the nervous system from early development throughout adulthood. TGF-ßs also influence synaptogenesis and neural network function. We have previously shown that TGF-ß2 may act as an important regulator in the establishment and functions of the respiratory neuronal network in the brain stem, one of the earliest CNS networks being established. In the immature brain, GABA is depolarizing and excitatory, whereas in the mature brain GABAA receptor-mediated responses are inhibitory and hyperpolarizing. This "developmental shift” in GABAergic neurotransmission during development is mainly controlled by the spatial and temporal expression of KCC2. To elucidate whether TGF-ß has a general role in the maturation and function of neuronal networks, the analysis will be extended to hippocampal networks. In the present proposal we want to elucidate the developmental requirement for TGF-ß2 in the KCC2-maturation of GABAergic synapses in the hippocampus, and investigate the biological significance of TGF-ß2 in the development and function of neuronal networks in vivo. Additionally, we will dissect the underlying molecular basis of TGF-ß2-mediated maturation of GABAergic neurotransmission.

TGF-β是多功能的细胞外信号分子，从早期发育到整个成年期在神经系统中起作用。TGF-β还影响突触发生和神经网络功能。我们先前已经表明，TGF-β 2可能在脑干中呼吸神经元网络的建立和功能中起重要调节剂的作用，所述呼吸神经元网络是最早建立的CNS网络之一。在未成熟的大脑中，GABA是去极化和兴奋性的，而在成熟的大脑中，GABAA受体介导的反应是抑制性和超极化的。在发育过程中GABA能神经传递的这种“发育转变”主要由KCC 2的时空表达控制。为了阐明TGF-β在神经元网络的成熟和功能中是否具有一般作用，分析将扩展到海马网络。在本研究中，我们希望阐明TGF-β 2在海马GABA能突触KCC 2成熟中的发育需要，并研究TGF-β 2在体内神经元网络发育和功能中的生物学意义。此外，我们将剖析TGF-β 2介导的GABA能神经传递成熟的潜在分子基础。