A role for p11 in the antidepressant action of brain-derived neurotrophic factor.
BACKGROUND
The protein p11 (also called S100A10) is downregulated in human and rodent depressive-like states. Considerable experimental evidence also implicates p11 in the mechanism of action of antidepressant drugs and electroconvulsive seizures, in part due to its interaction with specific serotonin receptors. Brain-derived neurotrophic factor (BDNF) has been linked to the therapeutic activity of antidepressants in rodent models and humans. In the current study, we investigated whether BDNF regulates p11 in vitro and in vivo.


METHODS
We utilized primary neuronal cultures, in vivo analyses of transgenic mice, and behavioral techniques to assess the effects of BDNF on p11.


RESULTS
Results indicate that BDNF stimulates p11 expression through tropomyosin-related kinase B (trkB) receptors and via the mitogen-activated protein kinase signaling pathway. Brain-derived neurotrophic factor-induced changes in p11 in vivo correlate with changes in ligand binding to the 5-hydroxytryptamine receptor 1B, the subcellular localization of which is known to be regulated by p11. Behavioral studies demonstrate that p11 knockout mice are insensitive to the antidepressant actions of BDNF.


CONCLUSIONS
Taken together, our data demonstrate that p11 levels are regulated by BDNF in vitro and in vivo and that the antidepressant-like effect of BDNF in two well-established behavioral models requires p11. These data support a role for p11 in the antidepressant activity of neurotrophins.
Warner-Schmidt
Jennifer L
JL
The Rockefeller University, New York, New York, USA. jschmidt@rockefeller.edu
Chen
Emily Y
EY
Zhang
Xiaoqun
X
Marshall
John J
JJ
Morozov
Alexei
A
Svenningsson
Per
P
Greengard
Paul
P
D000818:Animals; D017306:Annexin A2 / Q000096:biosynthesis*; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D018929:Cell Culture Techniques; D015283:Citalopram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D009418:S100 Proteins / Q000096:biosynthesis*; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000099248:S100 Calcium Binding Protein A10
D017306:Annexin A2; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D015283:Citalopram; D009418:S100 Proteins; D012701:Serotonin; D000099248:S100 Calcium Binding Protein A10