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Cortical Neurons Underlying Antidepressant Effects Identified

29 May 2012. Researchers have identified the cortical neurons that mediate antidepressant responses, according to a report appearing online May 25 in Cell. A team of scientists led by Nathaniel Heintz of New York’s Rockefeller University report that layer 5 corticostriatal pyramidal neurons expressing the adaptor protein p11 exhibit a robust response to treatment with the antidepressant fluoxetine, including an upregulation of serotonin receptors, that is p11 dependent.

Major depressive disorder (MDD) is known to involve a dysregulation of a number of brain regions involved in mood, including the prefrontal cortex, basal ganglia, and amygdala (Drevets, 2000). Serotonin is a key player in MDD, and selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants. However, the mechanisms underlying the pathology of MDD and the targets of successful treatments are thought to involve distinct brain areas. Thus, characterization of not only the pathophysiology of the illness, but also the cell types and molecular mechanisms that mediate the antidepressant response, are crucial to the development of novel treatment strategies.

One protein recently implicated in the antidepressant response is p11. Encoded by the S100a10 gene, p11 controls serotonin signaling through interactions with serotonin receptors that target them to the cell surface. Lower levels of p11 have been found in the cortex of patients with MDD as well as in a mouse model of the illness, and antidepressants increase the levels of p11 in mice (see SRF related news story). In the present study, Heintz and his group investigated whether cortical cells that express p11 are important in the action of antidepressants.

Characterizing cells
First author Eric Schmidt and colleagues used the so-called “bacTRAP” approach to selectively assess S100a10 cells. Recently developed by this group, this method allows for expression profiling of individual cell types (Doyle et al., 2008) without needing to isolate single cells beforehand (Heiman et al., 2008). Instead, bacterial artificial chromosome (BAC) transgenic mice, in which an EGFP-tagged ribosomal transgene is expressed in a specific cell population, are used for subsequent affinity purification and quantification of the mRNAs expressed within that cell type.

Using this approach, the researchers found that the majority of transgene expression occurred in pyramidal cells in superficial layer 5 of the cortex, and using retrograde tracing, they found that these S100a10 cells project to the dorsal striatum. All cells that expressed the transgene also contained p11. The S100a10-expressing pyramidal cells seem to be a previously uncharacterized cell population, as immunoprecipitates from these cells did not contain mRNAs such as Ntsr1, Etv1, and Glt25d2, which are found in other types of pyramidal cells.

Affecting antidepressant response
Using the SSRI fluoxetine (FLX), researchers then probed the role of S100a10 cells in the antidepressant response. Expression of cortical p11 was increased following two weeks of FLX treatment, and 62 different genes were differentially regulated by the drug after a slightly longer treatment. In contrast, the expression of only four genes was modulated by FLX in another population of pyramidal neurons, Glt25d2 cells, suggesting that the S100a10 cells are particularly sensitive to antidepressant treatment. Since p11 is known to affect serotonin receptor (5-Htr) function (see SRF related news story), the researchers next examined if 5-Htrs in S100a10 cells were changed following FLX treatment. Indeed, 5-Htr4 expression was increased in S100a10, but not Glt25d2, cells. The researchers hypothesize that this elevation in 5-Htr4 may make corticostriatal neurons more sensitive to the increased serotonin levels resulting from the drug, producing a beneficial increase in signaling from the cortex to the striatum.

To assess whether p11 played a role in the 5-Htr changes, the researchers then mated the S100a10 bacTRAP mice with p11 knockout animals, creating mice with p11 deleted from S100a10 cells (S100a10 p11 knockouts). Six different subtypes of 5-Htrs were downregulated in these animals, suggesting that a knockout of p11 produces a loss of serotonergic tone. Moreover, the knockout animals also failed to exhibit the dramatic response to FLX treatment observed in the S100a10 bacTRAP mice—most of the genes that were altered by FLX treatment in the S100a10 neurons were no longer changed in the S100a10 p11 knockouts.

Schmidt and colleagues then performed behavioral testing in cortex-specific p11 knockout mice to test the therapeutic effects of FLX treatment. In the novelty suppressed feeding paradigm, animals are placed in an open field with food in the center. Those treated with antidepressants take less time to approach the food in the novel environment than do untreated animals (Dulawa and Hen, 2005). However, in the current study, unlike wild-type animals, the cortex-specific p11 knockout mice did not exhibit a shorter latency to feed after treatment with FLX, indicating a diminished behavioral response to the antidepressant. Importantly, there were no alterations in baseline anxiety in the cortex-specific p11 knockouts, suggesting that the results reflect failure of these animals to respond to antidepressant treatment. Similar results were also observed using the tail suspension test, another task that is commonly used to assay antidepressant responses.

Taken together, the results of the current study demonstrate that S100a10-expressing corticostriatal projection neurons are critical for the molecular and behavioral responses of SSRIs. They also demonstrate the effectiveness of the bacTRAP translational profiling approach in detecting cell types that respond to drugs. The authors are hopeful that this approach will ultimately help patients, calling their study “an exciting step forward in the march toward development of more effective treatments for depression.”—Allison A. Curley.

Reference:
Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N. Identification of the Cortical Neurons that Mediate Antidepressant Responses. Cell . 2012 May 25 ; 149(5):1152-63. Abstract

Comments on News and Primary Papers
Comment by:  Lei ZhangDavid M. BenedekCarol S. FullertonRobert J. Ursano
Submitted 29 May 2012
Posted 29 May 2012

P11 (S100A10) in cortical neurons' response to antidepressants: A new story for p11
The potential role of p11 (S100A10) in the pathogenesis of psychiatric illness is gaining increasing interest in the neuroscience community. Recent studies suggest that p11 may be important in a number of disorders including posttraumatic disorder (PTSD) and depression (Su et al., 2009; Zhang et al., 2011; Zhang et al., 2008; Svenningsson and Greengard, 2007; Verma et al., 2007; Warner-Schmidt et al., 2009). P11 has been considered as a potential biomarker or therapeutic target for the treatment of depression and PTSD (Su et al., 2009; Zhang et al., 2011; Svenningsson and Greengard, 2007). However, the neuronal cell target or targets for p11-involved treatment in the central nervous system (CNS) remain unknown. In the current study, the authors find that corticostriatal projection neurons are the critical cells for the response to antidepressants in the CNS, and suggest that the regulation of serotonergic tone in this single cell type plays a pivotal role in antidepressant therapy. They also demonstrate that in corticostriatal pyramidal cells, p11 and serotonin receptor 4 are abundantly expressed, suggesting their strong and specific responses to chronic antidepressant treatment. As antidepressants are also a mainstay of PTSD treatment, their findings suggest that p11 may also mark treatment response in this disorder. Therefore, their findings of p11 action at the neuronal cellular level will facilitate the understanding of the pathology and drug development of stress-related mental disorders such as depression and PTSD.

References:

1. Su, T.P., et al. Levels of the potential biomarker p11 in peripheral blood cells distinguish patients with PTSD from those with other major psychiatric disorders. Journal of psychiatric research 43, 1078-1085 (2009). Abstract

2. Zhang, L., et al. P11 (S100A10) as a potential biomarker of psychiatric patients at risk of suicide. Journal of psychiatric research 45, 435-441 (2011). Abstract

3. Zhang, L., et al. p11 is up-regulated in the forebrain of stressed rats by glucocorticoid acting via two specific glucocorticoid response elements in the p11 promoter. Neuroscience 153, 1126-1134 (2008). Abstract

4. Svenningsson, P. and Greengard, P. p11 (S100A10)--an inducible adaptor protein that modulates neuronal functions. Current opinion in pharmacology 7, 27-32 (2007). Abstract

5. Verma, R., et al. Investigating the role of p11 (S100A10) sequence variation in susceptibility to major depression. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 144B, 1079-1082 (2007). Abstract

6. Warner-Schmidt, J.L., et al. Role of p11 in cellular and behavioral effects of 5-HT4 receptor stimulation. Journal of neuroscience 29, 1937-1946 (2009). Abstract

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Comments on Related News


Related News: A New Link between Serotonin and Depression

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 move away from the sides. These data are consistent with evidence that p11 is involved in modulating cellular pathways involved in depression-like and anxiety-like behavior. There are a number of additional behavioral tasks related to depression-like (e.g., forced swim test, learned helplessness) and anxiety-like (e.g., the elevated plus maze and black/white box) behavior, which could be studied in these mice. Additionally, the researchers used modern molecular and cellular biology, in addition to electrophysiological techniques, to strongly make the case that the behavioral changes likely involve interactions with the 5-HT1B receptor.

The authors “link” their basic science and rodent behavior data to humans by showing that both mRNA and protein levels of p11 are decreased in the postmortem brain of depressed patients compared to control subjects. Their finding that both ECT and imipramine increase p11 levels in the mouse brain suggests that similar effects could occur in humans. However, caution is warranted: The present field of psychiatric genetics was initiated with the understanding that human diseases are complex in nature—needing multiple genes working in disharmony with nongenetic contributors for the human syndrome. Thus, while a single gene disruption (e.g., p11) in the mouse may result in “human-related” psychiatric phenotypes, in humans, any involvement of p11 in the pathophysiology or treatment of mood disorders undoubtedly requires complex interactions with other susceptibility genes.

References:
Gould TD, Gottesman II (in press): Psychiatric endophenotypes and the development of valid animal models. Genes, Brain, and Behavior. (full text courtesy of Genes, Brain, and Behavior)

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Related 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