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Sci. Signal., 14 October 2008
Vol. 1, Issue 41, p. ra9
[DOI: 10.1126/scisignal.1162396]


BDNF Selectively Regulates GABAA Receptor Transcription by Activation of the JAK/STAT Pathway

Ingrid V. Lund1*, Yinghui Hu3,4*, YogendraSinh H. Raol2, Rebecca S. Benham3,4, Ramona Faris4,5, Shelley J. Russek4{dagger}, and Amy R. Brooks-Kayal6,7{dagger}

1 Neuroscience Graduate Group and Departments of Neurology and Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.
2 Division of Neurology, Children's Hospital, Philadelphia, PA 19104, USA.
3 Program in Biomedical Neurosciences, Boston University School of Medicine, Boston, MA 02118, USA.
4 Laboratory of Translational Epilepsy, Department of Pharmacology, Boston University School of Medicine, Boston, MA 02118, USA.
5 Laboratory of Molecular Neurobiology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA 02118, USA.
6 Division of Neurology, Department of Pediatrics, University of Colorado Denver School of Medicine, Denver, CO 80045, USA.
7 Division of Neurology, The Children's Hospital, 13123 East 16th Avenue, B155, Aurora, CO 80045, USA.

* These authors contributed equally to this work.

Abstract: The {gamma}-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 {alpha}1 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 {alpha}1 abundance in vivo and, given that BDNF is known to increase the abundance of GABAAR {alpha}4 in a JAK/STAT-independent manner, indicates that BDNF acts through at least two distinct pathways to influence GABAAR-dependent synaptic inhibition.

{dagger} To whom correspondence should be addressed. E-mail: srussek{at} (S.J.R.) and brooks-kayal.amy{at} (A.R.B.)

Citation: I. V. Lund, Y. Hu, Y. H. Raol, R. S. Benham, R. Faris, S. J. Russek, A. R. Brooks-Kayal, BDNF Selectively Regulates GABAA Receptor Transcription by Activation of the JAK/STAT Pathway. Sci. Signal. 1, ra9 (2008).

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