Non-hyperpolarizing GABAB receptor activation regulates neuronal migration and neurite growth and specification by cAMP/LKB1
Non-hyperpolarizing GABAB receptor activation regulates neuronal migration and neurite growth and specification by cAMP/LKB1
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DOI：
10.1038/ncomms2820
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发表时间：
2013-04-01
影响因子：
16.6
通讯作者：
Cancedda, Laura
中科院分区：
文献类型：
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作者：
Bony, Guillaume;Szczurkowska, Joanna;Cancedda, Laura
γ-氨基丁酸（GABA）是成人中的主要抑制性神经递质，通过亲离子氯渗透性GABA（A）受体（GABA（A）Rs）和亲代谢性GABA（B）Rs与钙或钾通道和cAMP信号传导偶联起作用。在早期发育期间，GABA是主要的神经递质，并且不是超极化的，因为GABA（A）R激活是去极化的，而GABA（B）Rs缺乏与钾通道的偶联。尽管对GABA（A）Rs作为神经元发育的关键因子有广泛的了解，但GABA（B）Rs的作用仍不清楚。在这里，我们解决GABA（B）R功能在大鼠皮质发育过程中，在子宫内敲低（短干扰RNA）的GABA（B）R的锥体神经元祖细胞。GABA（B）R敲低通过破坏cAMP信号传导损害神经元迁移和轴突/树突形态成熟。此外，GABA（B）R激活减少cAMP依赖性磷酸化LKB 1，一种参与神经元极化的激酶，并挽救LKB 1过表达诱导的皮质发育缺陷。因此，在发育过程中GABA（B）Rs的非超极化激活通过cAMP/LKB 1信号传导促进神经元迁移和形态成熟。
gamma-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in adults, acting through ionotropic chloride-permeable GABA(A) receptors (GABA(A)Rs), and metabotropic GABA(B)Rs coupled to calcium or potassium channels, and cAMP signalling. During early development, GABA is the main neurotransmitter and is not hyperpolarizing, as GABA(A)R activation is depolarizing while GABA(B)Rs lack coupling to potassium channels. Despite extensive knowledge on GABA(A)Rs as key factors in neuronal development, the role of GABA(B)Rs remains unclear. Here we address GABA(B)R function during rat cortical development by in utero knockdown (short interfering RNA) of GABA(B)R in pyramidal neuron progenitors. GABA(B)R knockdown impairs neuronal migration and axon/dendrite morphological maturation by disrupting cAMP signalling. Furthermore, GABA(B)R activation reduces cAMP-dependent phosphorylation of LKB1, a kinase involved in neuronal polarization, and rescues LKB1 overexpression-induced defects in cortical development. Thus, non-hyperpolarizing activation of GABA(B)Rs during development promotes neuronal migration and morphological maturation by cAMP/LKB1 signalling.