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

Brain-derived neurotrophic factor (BDNF) can regulate the maturation of dev eloping cerebellar granule neurons. Within 1-2 days of culture, BDNF induce s the expression of granule neuron terminal differentiation markers, partic ularly GABA(A) receptor alpha 6 subunit (GABA(A)alpha 6) mRNA. Other trophi c factors including insulin-like growth factor, the neurotrophin NT-3, pitu itary adenylate cyclase-activating polypeptide (PACAP), and fetal bovine se rum failed to induce this early expression. The expression of other GABA(A) receptor subunits, including alpha 1 and gamma 2, was also enhanced by exp osure of developing granule neurons to BDNF. This BDNF-dependent expression of GABA(A) receptor subunit mRNAs could be effectively blocked by treatmen t with the mitogen-activated protein kinase kinase (MEK) inhibitors, PD9805 9 or U0126. In the absence of BDNF, GABA(A)alpha 6 expression occurs but no t until 3-4 days of culture. This BDNF-independent expression of GABA(A)alp ha 6 was also inhibited by PD98059. Further studies showed that the BDNF-de pendent expression GABA(A)alpha 6 could also be reduced by LY294002, an inh ibitor of the phosphatidylinositol 3-kinase, or depolarizing concentrations of KCl. These results thus suggest that both BDNF-dependent and -independe nt expressions of GABA(A) receptor subunits require the activation of MEK a nd the mitogen-activated protein kinase (MAPK) pathway. However, it is also likely that other signaling pathways modulate this maturation process. (C) 2000 Elsevier Science B.V. All rights reserved.