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

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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.