title: Alteration by p11 of mGluR5 localization regulates depression-like behaviors.
abstract: Mood disorders and antidepressant therapy involve alterations of monoaminergic and glutamatergic transmission. The protein S100A10 (p11) was identified as a regulator of serotonin receptors, and it has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors. Here we report that p11 can also regulate depression-like behaviors via regulation of a glutamatergic receptor in mice. p11 directly binds to the cytoplasmic tail of metabotropic glutamate receptor 5 (mGluR5). p11 and mGluR5 mutually facilitate their accumulation at the plasma membrane, and p11 increases cell surface availability of the receptor. Whereas p11 overexpression potentiates mGluR5 agonist-induced calcium responses, overexpression of mGluR5 mutant, which does not interact with p11, diminishes the calcium responses in cultured cells. Knockout of mGluR5 or p11 specifically in glutamatergic neurons in mice causes depression-like behaviors. Conversely, knockout of mGluR5 or p11 in GABAergic neurons causes antidepressant-like behaviors. Inhibition of mGluR5 with an antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), induces antidepressant-like behaviors in a p11-dependent manner. Notably, the antidepressant-like action of MPEP is mediated by parvalbumin-positive GABAergic interneurons, resulting in a decrease of inhibitory neuronal firing with a resultant increase of excitatory neuronal firing. These results identify a molecular and cellular basis by which mGluR5 antagonism achieves its antidepressant-like activity.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: K-W
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Women's and Children's Health, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Westin
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Oh
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Amreen
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gresack
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Flajolet
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
authors.forename: D
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Women's and Children's Health, Science for Life Laboratory, Karolinska Institutet, Solna, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Aperia
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
authors.forename: P
authors.initials: P
authors.lastname: Greengard
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism*; D003863:Depression / Q000209:etiology*; D059330:GABAergic Neurons / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition; D009474:Neurons / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013569:Synapses; D000099248:S100 Calcium Binding Protein A10
chemical_list: D017306:Annexin A2; D018698:Glutamic Acid; D010320:Parvalbumins; D064529:Receptor, Metabotropic Glutamate 5; D009418:S100 Proteins; D000099248:S100 Calcium Binding Protein A10; C578936:Grm5 protein, mouse