BDNF Selectively Regulates GABA A Receptor Transcription by Activation of the JAK/STAT Pathway
- 14 October 2008
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 1 (41), ra9
- https://doi.org/10.1126/scisignal.1162396
Abstract
The γ-aminobutyric acid (GABA) type A receptor (GABAAR) is the major inhibitory neurotransmitter receptor in the brain. Its multiple subunits show regional, developmental, and disease-related plasticity of expression; however, the regulatory networks controlling GABAAR subunit expression remain poorly understood. We report that the seizure-induced decrease in GABAAR α1 subunit expression associated with epilepsy is mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway regulated by brain-derived neurotrophic factor (BDNF). BDNF- and seizure-dependent phosphorylation of STAT3 cause the adenosine 3′,5′-monophosphate (cAMP) response element–binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. JAK/STAT pathway inhibition prevents the seizure-induced decrease in GABAAR α1 abundance in vivo and, given that BDNF is known to increase the abundance of GABAAR α4 in a JAK/STAT-independent manner, indicates that BDNF acts through at least two distinct pathways to influence GABAAR-dependent synaptic inhibition.Keywords
This publication has 85 references indexed in Scilit:
- Surface Expression of GABAA Receptors Is Transcriptionally Controlled by the Interplay of cAMP-response Element-binding Protein and Its Binding Partner Inducible cAMP Early RepressorPublished by Elsevier BV ,2008
- CREB Binding and Activity in Brain: Regional Specificity and Induction by Electroconvulsive SeizureBiological Psychiatry, 2008
- The role of transcription factors cyclic-AMP responsive element modulator (CREM) and inducible cyclic-AMP early repressor (ICER) in epileptogenesisNeuroscience, 2008
- Diminished Neurosteroid Sensitivity of Synaptic Inhibition and Altered Location of the α4 Subunit of GABAAReceptors in an Animal Model of EpilepsyJournal of Neuroscience, 2007
- Reversal of neurosteroid effects at α4β2δ GABAA receptors triggers anxiety at pubertyNature Neuroscience, 2007
- CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticusNeurobiology of Disease, 2007
- Enhanced macroscopic desensitization shapes the response of α4 subtype‐containing GABAA receptors to synaptic and extrasynaptic GABAThe Journal of Physiology, 2007
- GluR‐ and TrkB‐mediated maturation of GABAA receptor function during the period of eye openingEuropean Journal of Neuroscience, 2005
- Transcriptional regulation by the phosphorylation-dependent factor CREBNature Reviews Molecular Cell Biology, 2001
- Developmental Expression of GABAA Receptor Subunit mRNAs in Individual Hippocampal Neurons In Vitro and In VivoJournal of Neurochemistry, 1998