CREB-Dependent Regulation of GAD65 Transcription by BDNF/TrkB in Cortical Interneurons.
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.
Sánchez-Huertas
Carlos
C
Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
Rico
Beatriz
B
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000096:biosynthesis* / Q000235:genetics; D015151:Immunoblotting; D007150:Immunohistochemistry; D007395:Interneurons / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020813:Receptor, trkB / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D020813:Receptor, trkB; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2