BDNF selectively regulates GABAA receptor transcription by activation of the JAK/STAT pathway

Sci Signal. 2008 Oct 14;1(41):ra9. doi: 10.1126/scisignal.1162396.

Abstract

The gamma-aminobutyric acid (GABA) type A receptor (GABA(A)R) 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 GABA(A)R subunit expression remain poorly understood. We report that the seizure-induced decrease in GABA(A)R alpha1 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 GABA(A)R alpha1 abundance in vivo and, given that BDNF is known to increase the abundance of GABA(A)R alpha4 in a JAK/STAT-independent manner, indicates that BDNF acts through at least two distinct pathways to influence GABA(A)R-dependent synaptic inhibition.

MeSH terms

  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism*
  • CREB-Binding Protein / genetics
  • CREB-Binding Protein / metabolism
  • Cyclic AMP Response Element Modulator / genetics
  • Cyclic AMP Response Element Modulator / metabolism
  • Epilepsy / genetics
  • Epilepsy / metabolism
  • Gene Expression Regulation*
  • Humans
  • Janus Kinases / genetics
  • Janus Kinases / metabolism*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / biosynthesis*
  • Receptors, GABA-A / genetics
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / genetics
  • Synaptic Membranes / genetics
  • Synaptic Membranes / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • CREM protein, human
  • Crem protein, rat
  • Receptors, GABA-A
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, rat
  • Cyclic AMP Response Element Modulator
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, rat
  • Janus Kinases