Brain-derived neurotrophic factor mitigates chronic ethanol-induced attenuation of gamma-aminobutyric acid responses in cultured cerebellar granule cells.
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.
Ericson
Mia
M
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Haythornthwaite
Alison R
AR
Yeh
Pamela W L
PW
Yeh
Hermes H
HH
D020268:Alcohol-Induced Disorders, Nervous System / Q000503:physiopathology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002531:Cerebellum / Q000502:physiology; D000431:Ethanol / Q000494:pharmacology*; D007150:Immunohistochemistry; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D021122:Protein Subunits / Q000187:drug effects / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D002492:Central Nervous System Depressants; D021122:Protein Subunits; D011963:Receptors, GABA-A; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D020813:Receptor, trkB