Ericson Mia, Haythornthwaite Alison R, Yeh Pamela W L, Yeh Hermes H
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
J Neurosci Res. 2003 Sep 1;73(5):722-30. doi: 10.1002/jnr.10694.
This study examined the effect of chronic exposure to ethanol and brain-derived neurotrophic factor (BDNF) on the responsiveness of cerebellar granule cells to gamma-aminobutyric acid (GABA). Cerebellar granule cell cultures were chronically exposed to ethanol (100 mM), BDNF (20 ng/ml), or the combination of ethanol and BDNF. Whole-cell current responses of granule cells to exogenously applied GABA were monitored following at least 5 days of chronic exposure. In the ethanol-treated cultures, granule cell responsiveness to GABA was attenuated. Concomitant exposure of cultures to ethanol and BDNF mitigated the ethanol-induced attenuation of GABA response, although BDNF, by itself, did not affect responsiveness to GABA. BDNF increased the expression of the GABA(A) receptor alpha6 subunit, whereas ethanol had no effect, in chronically treated granule cell cultures. In addition, concomitant treatment with BDNF and ethanol did not increase the expression of the GABA(A) receptor alpha6 subunit, so the subunit expression alone could not account for the mitigating effect of BDNF. We propose that different mechanisms regulating responsiveness to GABA underlie the effects induced by ethanol and BDNF, with the former influencing the expression of functional GABA(A) receptors and the latter involving the activation of the TrkB receptor and its downstream signaling pathways.
本研究考察了长期暴露于乙醇和脑源性神经营养因子（BDNF）对小脑颗粒细胞对γ-氨基丁酸（GABA）反应性的影响。将小脑颗粒细胞培养物长期暴露于乙醇（100 mM）、BDNF（20 ng/ml）或乙醇与BDNF的组合中。在至少5天的长期暴露后，监测颗粒细胞对外源性应用GABA的全细胞电流反应。在乙醇处理的培养物中，颗粒细胞对GABA的反应性减弱。培养物同时暴露于乙醇和BDNF可减轻乙醇诱导的GABA反应减弱，尽管单独的BDNF并不影响对GABA的反应性。在长期处理的颗粒细胞培养物中，BDNF增加了GABA(A)受体α6亚基的表达，而乙醇则无此作用。此外，BDNF和乙醇联合处理并未增加GABA(A)受体α6亚基的表达，因此仅亚基表达不能解释BDNF的减轻作用。我们提出，乙醇和BDNF诱导的效应背后存在调节对GABA反应性的不同机制，前者影响功能性GABA(A)受体的表达，后者涉及TrkB受体及其下游信号通路的激活。
