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Annotation

Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science . 2006 Jan 6 ; 311(5757):77-80. PubMed Abstract

Comments on Paper and Primary News
Primary News: A New Link between Serotonin and Depression

Comment by:  Todd Gould
Submitted 13 January 2006 Posted 14 January 2006
  I recommend this paper

Proof that model organisms can “suffer” from psychiatric illness is at very best modest. However, the use of animal models gets around this either through symptom modeling or studying endophenotypes (see recent SRF endophenotype discussion and Gould and Gottesman, 2005). Thus, only facets, whether they be face valid “re-creations” of symptoms or models of inherent and quantifiable measures of brain functions, are utilized.

The recent paper by Svennignsson, Greengard, and colleagues takes advantage of these approaches to describe a novel function of p11, namely, the modulation of depression-like states. This includes increased tail suspension test (TST) immobility in mice where p11 has been removed (knockout; KO mice), and decreased TST immobility in mice that overexpress p11. Further, p11 KO mice spent more time along the “safer” sides of an open field, while mice overexpressing p11 tended to...  Read more


View all comments by Todd Gould

Comment by:  Guang ChenHusseini K. Manji
Submitted 15 January 2006 Posted 15 January 2006

The recent manuscript from Per Svenningsson’s laboratory at the Karolinska Institute in Stockholm, and Paul Greengard’s laboratory at the Rockefeller University in New York has identified a molecule—p11—as a putative mediator of depressive states, and as a target of antidepressant drug action.

The major strength of the study is the diverse array of methodologies/paradigms utilized to provide convergent data. Thus, they used a yeast two-hybrid system, transfected cells, selectively bred animals, and transgenic and knockout animals, and even human postmortem brain samples. They report that the p11 protein mediates 5-HT1B receptor surfacing, 5-HT1B receptor-induced inhibition of the cAMP pathway and the ERK pathway, fEPSP, and 5-HT turnover. Importantly, they show that mRNA and/or protein levels of p11 are different in groups of sham versus antidepressant treated animals, non-helpless versus helpless selectively bred animals, and control versus depression patients’ postmortem brain tissue. Furthermore, transgenic mice potentially overexpressing p11 proteins...  Read more


View all comments by Guang Chen
View all comments by Husseini K. Manji

Comment by:  Etienne Sibille
Submitted 17 January 2006 Posted 17 January 2006

As the 5-HT system is involved in the pathology and pharmacological treatment of depression, any new evidence for genes or molecules regulating its function has putative implication for mechanisms and/or treatment of depression. Here, Svenningsson et al. provide compelling evidence about the identification and role of p11 in mediating some of the downstream effects of 5-HT1B receptor signaling. In particular, the authors, using several complementary approaches, demonstrate that p11 levels correlate with 5-HT1B receptor level and function at the membrane. Thus, p11 levels may be considered an “index” of 5-HT1B receptor function. Furthermore, manipulations that increase 5-HT function (i.e., chronic antidepressant treatment and ECT) up-regulate p11 levels, possibly responding to increased demand on 5-HT1B function to regulate presynaptic release. The fact that these up-and-down manipulations of p11 correlate with behaviors in the mouse that have been associated either with changes that occur after antidepressant treatment or in “depression-like” or increased fearfulness states...  Read more


View all comments by Etienne Sibille

Comment by:  Patricia Estani
Submitted 17 January 2006 Posted 17 January 2006
  I recommend this paper

Primary News: A New Link between Serotonin and Depression

Comment by:  Mary Reid
Submitted 21 January 2006 Posted 23 January 2006

It's most interesting that Paul Greengard and colleagues report lower levels of p11 in brain samples from depressed patients. Renegunta et al. report that knockdown of p11 with siRNA enhanced trafficking of TASK-1 to the surface membrane. Hopwood et al. find that present data suggest that the excitatory effects of 5-HT on DVN are mediated in part by inhibition of a TASK-like, pH-sensitive K+ conductance, and the Perrier group reports that 5-HT1A receptors inhibit TASK-1-like K+ current in the adult turtle. Might we suspect that a specific inhibitor of TASK-1 conductance would be beneficial in depression, and might this in part explain the benefit reported by SSRIs and agents with 5-HT1A receptor agonist activity in the treatment of depression?

References:
Renigunta V, Yuan H, Zuzarte M, Rinne S, Koch A, Wischmeyer E, Schlichthorl G, Gao Y, Karschin A, Jacob R, Schwappach B, Daut J, Preisig-Muller R. The Retention Factor p11 Confers an Endoplasmic Reticulum-Localization Signal to the Potassium Channel TASK-1. Traffic. 2006 Feb;7(2):168-81. Abstract

Hopwood SE, Trapp S. TASK-like K+ channels mediate effects of 5-HT and extracellular pH in rat dorsal vagal neurones in vitro. J Physiol. 2005 Oct 1;568(Pt 1):145-54. Epub 2005 Jul 14. Abstract

Perrier JF, Alaburda A, Hounsgaard J. 5-HT1A receptors increase excitability of spinal motoneurons by inhibiting a TASK-1-like K+ current in the adult turtle. J Physiol. 2003 Apr 15;548(Pt 2):485-92. Epub 2003 Mar 7. Abstract

View all comments by Mary Reid

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