Brain-derived neurotrophic factor exerts opposing effects on beta(2)-adrenergic receptor according to depolarization status of cerebellar neurons

To investigate the molecular mechanisms underlying brain-derived neurotroph ic factor (BDNF)-controlled synaptic plasticity, we studied beta(2)-adrener gic receptor (beta(2)-AR) expression in cultured cerebellar granule cells. We show that, depending on the state of depolarization, BDNF exerts opposit e effects on beta(2)-AR expression. In neurons maintained in low Kt medium (5 mM K+) that will enter apoptosis, BDNF increases beta(2)-AR and beta(2)- AR transcripts, In contrast, in depolarized neurons (high K+ medium, 25 mM K+) BDNF represses beta(2)-AR expression. The use of reporter genes (driven by the beta(2)-AR promoter or restricted regulatory elements) revealed tha t BDNF exerts its opposite effects at the transcriptional level by recruiti ng a cyclic AMP response element (CRE) and the trans-acting factor CRE bind ing protein. These results provide the first evidence that a neurotrophin, e.g., BDNF, may exert an opposite effect on receptor expression and functio n (beta(2)-AR) according to the depolarization status of the neuron. Based on this finding, we propose that BDNF not only mediates neuronal survival, but is also involved in the modulation of the general sensitivity of the ne uron to external signals, thus maintaining its optimal functional integrati on within the neuronal network.