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The Journal of Neuroscience, January 14, 2004, 24(2):522-530; doi:10.1523/JNEUROSCI.3606-03.2004

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Cellular/Molecular
Brain-Derived Neurotrophic Factor Modulates Fast Synaptic Inhibition by Regulating GABA_A Receptor Phosphorylation, Activity, and Cell-Surface Stability

Jasmina N. Jovanovic,¹ Philip Thomas,¹ Josef T. Kittler,¹ Trevor G. Smart,¹ and Stephen J. Moss^1,2

¹Department of Pharmacology, University College, London, WC1E 6BT, United Kingdom, and ²Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The efficacy of GABAergic synaptic inhibition is a principal factor in controlling neuronal activity. We demonstrate here that brain-derived neurotrophic factor modulates the activity of GABA_A receptors, the main sites of fast synaptic inhibition in the brain, within minutes of application. Temporally, this comprised an early enhancement in the miniature IPSC amplitude, followed by a prolonged depression. This modulation was concurrent with enhanced PKC-mediated phosphorylation, followed by protein phosphatase 2A (PP2A)-mediated dephosphorylation of the GABA_A receptor. Mechanistically, these events were facilitated by differential recruitment of PKC, receptor for activated C-kinase, and PP2A to GABA_A receptors, depending on the phosphorylation state of the receptor ₃-subunit. Thus, transient formation of GABA_A receptor signaling complexes has the potential to provide a basis for acute changes in receptor function underlying GABAergic synaptic plasticity.

Key words: GABA; growth factor; phosphatase; phosphorylation; protein kinase; synaptic

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Received Aug 1, 2003; revised November 3, 2003; accepted November 3, 2003.

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