FMRP regulates an ethanol-dependent shift in GABABR function and expression with rapid antidepressant properties.
Alcohol promotes lasting neuroadaptive changes that may provide relief from depressive symptoms, often referred to as the self-medication hypothesis. However, the molecular/synaptic pathways that are shared by alcohol and antidepressants are unknown. In the current study, acute exposure to ethanol produced lasting antidepressant and anxiolytic behaviours. To understand the functional basis of these behaviours, we examined a molecular pathway that is activated by rapid antidepressants. Ethanol, like rapid antidepressants, alters γ-aminobutyric acid type B receptor (GABABR) expression and signalling, to increase dendritic calcium. Furthermore, new GABABRs are synthesized in response to ethanol treatment, requiring fragile-X mental retardation protein (FMRP). Ethanol-dependent changes in GABABR expression, dendritic signalling, and antidepressant efficacy are absent in Fmr1-knockout (KO) mice. These findings indicate that FMRP is an important regulator of protein synthesis following alcohol exposure, providing a molecular basis for the antidepressant efficacy of acute ethanol exposure.
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas 78712, USA.|Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
Sarah A
SA
Wolfe
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
Emily R
ER
Workman
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
Chelcie F
CF
Heaney
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
Farr
F
Niere
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.
Sanjeev
S
Namjoshi
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
Luisa P
LP
Cacheaux
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
Sean P
SP
Farris
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
Michael R
MR
Drew
Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
Boris V
BV
Zemelman
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.
R Adron
RA
Harris
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas 78712, USA.|Center for Learning and Memory, The University of Texas at Austin, Austin, Texas 78712, USA.|Institute of Cell and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Neuroscience, The University of Texas at Austin, Austin, Texas 78712, USA.|Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27101, USA.
Kimberly F
KF
Raab-Graham
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