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A New Link between Serotonin and Depression

12 January 2006. There is a new link between serotonin and depression—it is a tiny protein of only 97 amino acids called p11. In the January 6 Science, Paul Greengard and colleagues at The Rockefeller University, New York, reported that p11 plays a key role in localizing 5-hydroxytryptmine 1B (5-HT1B) neuroreceptors to the cell surface, where they facilitate serotonergic transmission. Perhaps more importantly, the authors also report that levels of p11 are lower in brain samples taken from depressed patients, and that in animal models, tricyclic antidepressants or electroconvulsive therapy boosts levels of the protein in the brain. The findings could lead to a better understanding of the causes of depression, as well as point to more effective treatments, and may prove beneficial to the substantial number of schizophrenia patients who suffer from depression.

Most antidepressants work by increasing levels of serotonin, which is crucial for controlling mood. The specifics of serotonin’s role in depressed states have remained elusive, partly because there are at least 14 different types of serotonin receptor, each interacting with a plethora of other proteins that may have modulating effects. The 5-HT1B subtype is particularly interesting, however, because it is both an autoreceptor, appearing on neurons that make serotonin, and a heteroreceptor, found on projection neurons that are stimulated by serotonin-producing neurons. These are thought to modulate and facilitate, respectively, communication between neurons. 5-HT1B receptors have also been implicated in the pathology of a variety of psychiatric conditions, such as obsessive-compulsive disorder, anxiety, and aggression (see review by Moret and Briley, 2000).

In order to learn more about this receptor, first author Per Svenningsson and colleagues used the classic yeast two-hybrid screen to search for proteins that might bind to, and modulate, its activity. Using one of the intracellular loops of the receptor as “bait,” the authors fished out 29 clones, of which 26 turned out to harbor p11 cDNA. The interaction between the two proteins appears to be quite specific, because baits made from 5-HT1A, 5-HT2A, 5-HT5A, and 5-HT6 receptors, or baits using the dopamine D1 or D2 receptors, failed to attract the protein.

What affect might this small protein have on serotonin receptors? Clues to the role of p11 come from studies showing that it regulates translocation of transmembrane proteins to the cell surface. This may also be how it modulates 5-HT1B receptors, because when Svenningsson and colleagues transfected 5-HT1B-producing cells with p11 DNA, more of the serotonin receptors ended up at the cell membrane, and they appeared to be functional: 5-HT1B inhibits adenyl cyclase activity and in cells expressing p11, cyclic AMP production in response to forskolin was attenuated.

These data led the authors to examine the potential role of p11 in depression. They found modest though significant reductions in levels of p11 messenger RNA (15 percent lower) and protein (about 20 percent) in postmortem samples of anterior cingulate cortex from patients who had suffered from unipolar major depression. They also found that levels of the protein are markedly reduced in H/Rouen mice, a genetic model of depression. Furthermore, they found that p11 knockout mice had significantly fewer 5-HT1B receptors and exhibited a depressionlike phenotype, including decreased appetite, while animals overexpressing p11 behaved as if they were on antidepressants. In fact, when the authors used electroconvulsive therapy or administered the tricyclic antidepressant imipramine to mice, levels of p11 mRNA in the forebrain increased by 30 percent.

“Overall, this finding represents compelling evidence that p11 has a pivotal role in both the cause of depression and perhaps its successful treatment,” writes Trevor Sharp from the University of Oxford, England, in an accompanying Science perspective. In this regard, it might be worthwhile pursuing the development of drugs that can boost levels of p11. Of course, this would not necessarily represent a panacea for depression because other components of the serotonin signaling pathway, such as the serotonin transporter and other 5-HT receptors have also been implicated in the pathology of this condition (for a review, see Stockmeier, 2003).—Tom Fagan.

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

Comments on News and Primary Papers
Comment by:  Todd Gould
Submitted 13 January 2006 Posted 14 January 2006
  I recommend the Primary Papers

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

Primary Papers: Alterations in 5-HT1B receptor function by p11 in depression-like states.

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

Primary Papers: Alterations in 5-HT1B receptor function by p11 in depression-like states.

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

Primary Papers: Alterations in 5-HT1B receptor function by p11 in depression-like states.

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

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?

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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