Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
Cereb Cortex. 2011 Apr;21(4):777-88. doi: 10.1093/cercor/bhq150. Epub 2010 Aug 25.
In the cerebral cortex, the functional output of projection neurons is fine-tuned by inhibitory neurons present in the network, which use γ-aminobutyric acid (GABA) as their main neurotransmitter. Previous studies have suggested that the expression levels of the rate-limiting GABA synthetic enzyme, GAD65, depend on brain derived neurotrophic factor (BDNF)/TrkB activation. However, the molecular mechanisms by which this neurotrophic factor and its receptor controls GABA synthesis are still unknown. Here, we show a direct regulation of the GAD65 gene by BDNF-TrkB signaling via CREB in cortical interneurons. Conditional ablation of TrkB in cortical interneurons causes a cell-autonomous decrease in the synaptically enriched GAD65 protein and its transcripts levels, suggesting that transcriptional regulation of the GAD65 gene is altered. Dissection of the intracellular pathway that underlies this process revealed that BDNF/TrkB signaling controls the transcription of GAD65 in a Ras-ERK-CREB-dependent manner. Our study reveals a novel molecular mechanism through which BDNF/TrkB signaling may modulate the maturation and function of cortical inhibitory circuits.
在大脑皮层中，投射神经元的功能输出受到网络中存在的抑制性神经元的微调，这些神经元使用γ-氨基丁酸（GABA）作为它们的主要神经递质。先前的研究表明，限速 GABA 合成酶 GAD65 的表达水平取决于脑源性神经营养因子（BDNF）/TrkB 的激活。然而，这种神经营养因子及其受体控制 GABA 合成的分子机制尚不清楚。在这里，我们显示了 BDNF-TrkB 信号通过 CREB 在皮质中间神经元中对 GAD65 基因的直接调节。皮质中间神经元中 TrkB 的条件性缺失导致突触丰富的 GAD65 蛋白及其转录物水平的自主减少，表明 GAD65 基因的转录调节发生了改变。对该过程所涉及的细胞内途径的剖析表明，BDNF/TrkB 信号通过 Ras-ERK-CREB 依赖性方式控制 GAD65 的转录。我们的研究揭示了一种新的分子机制，通过该机制，BDNF/TrkB 信号可能调节皮质抑制回路的成熟和功能。
