Short-term striatal gene expression responses to brain-derived neurotrophic factor are dependent on MEK and ERK activation.
BACKGROUND
Brain-derived neurotrophic factor (BDNF) is believed to be an important regulator of striatal neuron survival, differentiation, and plasticity. Moreover, reduction of BDNF delivery to the striatum has been implicated in the pathophysiology of Huntington's disease. Nevertheless, many essential aspects of BDNF responses in striatal neurons remain to be elucidated.


RESULTS
In this study, we assessed the relative contributions of multipartite intracellular signaling pathways to the short-term induction of striatal gene expression by BDNF. To identify genes regulated by BDNF in these GABAergic cells, we first used DNA microarrays to quantify their transcriptomic responses following 3 h of BDNF exposure. The signal transduction pathways underlying gene induction were subsequently dissected using pharmacological agents and quantitative real-time PCR. Gene expression responses to BDNF were abolished by inhibitors of TrkB (K252a) and calcium (chelator BAPTA-AM and transient receptor potential cation channel [TRPC] antagonist SKF-96365). Interestingly, inhibitors of mitogen-activated protein kinase kinases 1 and 2 (MEK1/2) and extracellular signal-regulated kinase ERK also blocked the BDNF-mediated induction of all tested BDNF-responsive genes. In contrast, inhibitors of nitric oxide synthase (NOS), phosphotidylinositol-3-kinase (PI3K), and CAMK exhibited less prevalent, gene-specific effects on BDNF-induced RNA expression. At the nuclear level, the activation of both Elk-1 and CREB showed MEK dependence. Importantly, MEK-dependent activation of transcription was shown to be required for BDNF-induced striatal neurite outgrowth, providing evidence for its contribution to striatal neuron plasticity.


CONCLUSIONS
These results show that the MEK/ERK pathway is a major mediator of neuronal plasticity and other important BDNF-dependent striatal functions that are fulfilled through the positive regulation of gene expression.
Gokce
Ozgun
O
Laboratory of Functional Neurogenomics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Runne
Heike
H
Kuhn
Alexandre
A
Luthi-Carter
Ruth
R
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015870:Gene Expression; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009473:Neuronal Plasticity; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D002118:Calcium