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 has been implicated in the etiology of depression and in mediating the antidepressant actions of selective serotonin reuptake inhibitors (SSRIs). 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 membranes, and p11 increases cell surface availability of the receptor. While 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, 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.

Gene therapy blockade of dorsal striatal p11 improves motor function and dyskinesia in parkinsonian mice

“…p11 also has been reported to interact with SMARCA3, a chromatin remodeling factor, and this interaction appears to be important for some antidepressant effects of p11 (19). Most relevant to our current findings, however, is a recent report of p11 binding to the mGluR5 metabotropic glutamate receptor (20). In prefrontal cortex, p11 was found to potentiate the effects of mGluR5 to regulate depression-like behaviors.…”

p11 modulates L-DOPA therapeutic effects and dyskinesia via distinct cell types in experimental Parkinsonism

“…It is possible that p11 modulates L-DOPA responses by altering serotonin and glutamate neurotransmission. p11 facilitates signal transduction via serotonin 5-HT 1B R and 5-HT 4 R and glutamate mGluR5 (4,5). Preclinical studies (10,20) have shown that 5-HT 1B R agonism counteracts L-DOPA responses via inhibition of release of "false dopamine" from serotonin terminals (20) and by counteracting D1-mediated signaling in striatonigral neurons (10).…”

“…p11 (i.e., S100A10) is a member of the S100 EF-hand protein family, which increase the levels of distinct serotonin (5-HT 1B R and 5-HT 4 R) and glutamate (mGluR5) receptors at the cell surface, resulting in enhanced effects on cell signaling via these receptors (4,5). p11 is widely expressed in the brain with particularly high levels in cholinergic neurons (6)(7)(8)(9).…”

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

“…30 The mGluR1 and mGluR5 dimers presented as 2 bands (270-280 kDa; quantified together as the dimer), whereas the monomer presented as a single band (150 kDa). We and others have previously reported this pattern of bands for group 1 mGluRs, 29,31,32 including the use of alternate mGluR1 and mGluR5 antibodies, and specificity has been confirmed using respective KO mice. 32,33 The mGluR1 dimeric and monomeric bands appeared at similar intensities.…”