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

转化生长因子-βS是多功能的细胞外信号分子，作用于神经系统，从早期发育到成年期。转化生长因子--S也影响突触发生和神经网络功能。我们之前已经证明，在脑干呼吸神经网络的建立和功能中，转化生长因子-2可能是一个重要的调节因子，这是最早建立的中枢神经网络之一。在未成熟的大脑中，GABA是去极化和兴奋的，而在成熟的大脑中，GABAA受体介导的反应是抑制和超极化的。在发育过程中，GABA能神经传递的这种“发育转变”主要由KCC2的时空表达控制。为了阐明转化生长因子-β是否在神经元网络的成熟和功能中起着普遍的作用，我们将把分析扩展到海马区的网络。在本研究中，我们想要阐明在KCC2--GABA能突触的成熟过程中对转化生长因子--2的发育要求，并探讨转化生长因子--2在体内神经网络的发育和功能中的生物学意义。此外，我们还将剖析转化生长因子-β2介导的GABA能神经传递成熟的分子基础。

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.