MEK inhibitors block BDNF-dependent and -independent expression of GABA A receptor subunit mRNAs in cultured mouse cerebellar granule neurons

• Published in: Brain research. Developmental brain research 2000-01, Vol.119 (1), p.1-10
• Main Authors: Bulleit, Robert F, Hsieh, Ted
• Format: Article
• Language: English
• Subjects: Animals; Blood Proteins - pharmacology; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Brain-Derived Neurotrophic Factor - pharmacology; Calcium Channel Blockers - pharmacology; Cell Differentiation - physiology; Cells, Cultured; Cerebellar granule neuron; Cerebellum - cytology; Cerebellum - physiology; Chromones - pharmacology; Cytomegalovirus - genetics; Cytoplasmic Granules; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; GABA A receptor; Gene expression; Gene Expression Regulation - physiology; Genes, Reporter; Insulin-Like Growth Factor I - pharmacology; MAP Kinase Kinase 1; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Maturation; Mice; Mitogen-activated protein kinase; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Morpholines - pharmacology; Neurons - cytology; Neurons - enzymology; Neuropeptides - pharmacology; Neurotrophin 3 - pharmacology; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Pituitary Adenylate Cyclase-Activating Polypeptide; Promoter Regions, Genetic - genetics; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Receptors, GABA-A - genetics; RNA, Messenger - biosynthesis; Veratridine - pharmacology
• ISSN: 0165-3806
• DOI: 10.1016/S0165-3806(99)00119-4

Brain-derived neurotrophic factor (BDNF) can regulate the maturation of developing cerebellar granule neurons. Within 1–2 days of culture, BDNF induces the expression of granule neuron terminal differentiation markers, particularly GABA A receptor α6 subunit (GABA Aα6) mRNA. Other trophic factors including insulin-like growth factor, the neurotrophin NT-3, pituitary adenylate cyclase-activating polypeptide (PACAP), and fetal bovine serum failed to induce this early expression. The expression of other GABA A receptor subunits, including α1 and γ2, was also enhanced by exposure of developing granule neurons to BDNF. This BDNF-dependent expression of GABA A receptor subunit mRNAs could be effectively blocked by treatment with the mitogen-activated protein kinase kinase (MEK) inhibitors, PD98059 or U0126. In the absence of BDNF, GABA Aα6 expression occurs but not until 3–4 days of culture. This BDNF-independent expression of GABA Aα6 was also inhibited by PD98059. Further studies showed that the BDNF-dependent expression GABA Aα6 could also be reduced by LY294002, an inhibitor of the phosphatidylinositol 3-kinase, or depolarizing concentrations of KCl. These results thus suggest that both BDNF-dependent and -independent expressions of GABA A receptor subunits require the activation of MEK and the mitogen-activated protein kinase (MAPK) pathway. However, it is also likely that other signaling pathways modulate this maturation process.