The ability of BDNF to modify neurogenesis and depressive-like behaviors is dependent upon phosphorylation of tyrosine residues 365/367 in the GABA(A)-receptor γ2 subunit.
Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal activity, neurogenesis, and depressive-like behaviors; however, downstream effectors by which BDNF exerts these varying actions remain to be determined. Here we reveal that BDNF induces long-lasting enhancements in the efficacy of synaptic inhibition by stabilizing γ2 subunit-containing GABA(A) receptors (GABA(A)Rs) at the cell surface, leading to persistent reductions in neuronal excitability. This effect is dependent upon enhanced phosphorylation of tyrosines 365 and 367 (Y365/7) in the GABA(A)R γ2 subunit as revealed using mice in which these residues have been mutated to phenyalanines (Y365/7F). Heterozygotes for this mutation exhibit an antidepressant-like phenotype, as shown using behavioral-despair models of depression. In addition, heterozygous Y365/7F mice show increased levels of hippocampal neurogenesis, which has been strongly connected with antidepressant action. Both the antidepressant phenotype and the increased neurogenesis seen in these mice are insensitive to further modulation by BDNF, which produces robust antidepressant-like activity and neurogenesis in wild-type mice. Collectively, our results suggest a critical role for GABA(A)R γ2 subunit Y365/7 phosphorylation and function in regulating the effects of BDNF.
Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom, Department of Neuroscience, Tufts University, Boston, Massachusetts 02111, AstraZeneca Pharmaceuticals, Cambridge, Massachusetts 02139, and Department of Physiology and Biophysics, University at Buffalo, State University of New York, Buffalo, New York 14214.
Mansi
M
Vithlani
Rochelle M
RM
Hines
Ping
P
Zhong
Miho
M
Terunuma
Dustin J
DJ
Hines
Raquel
R
Revilla-Sanchez
Rachel
R
Jurd
Phillip
P
Haydon
Maribel
M
Rios
Nicholas
N
Brandon
Zhen
Z
Yan
Stephen J
SJ
Moss
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology* / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy* / Q000235:genetics; D006579:Heterozygote; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D010641:Phenotype; D010766:Phosphorylation; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; C546280:Gabrg2 protein, mouse; D021122:Protein Subunits; D011963:Receptors, GABA-A; D014443:Tyrosine