Identification of the Cortical Neurons That Mediate Antidepressant Responses

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2012 May 29

PMID 22632977

Citations 81

Authors

Eric F Schmidt

Jennifer L Warner-Schmidt

Benjamin G Otopalik

Sarah B Pickett

Paul Greengard

Nathaniel Heintz

Affiliations

Soon will be listed here.

Abstract

Our understanding of current treatments for depression, and the development of more specific therapies, is limited by the complexity of the circuits controlling mood and the distributed actions of antidepressants. Although the therapeutic efficacy of serotonin-specific reuptake inhibitors (SSRIs) is correlated with increases in cortical activity, the cell types crucial for their action remain unknown. Here we employ bacTRAP translational profiling to show that layer 5 corticostriatal pyramidal cells expressing p11 (S100a10) are strongly and specifically responsive to chronic antidepressant treatment. This response requires p11 and includes the specific induction of Htr4 expression. Cortex-specific deletion of p11 abolishes behavioral responses to SSRIs, but does not lead to increased depression-like behaviors. Our data identify corticostriatal projection neurons as critical for the response to antidepressants, and suggest that the regulation of serotonergic tone in this single cell type plays a pivotal role in antidepressant therapy.

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References

Warner-Schmidt J, Chen E, Zhang X, Marshall J, Morozov A, Svenningsson P . A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry. 2010; 68(6):528-35. PMC: 2929288. DOI: 10.1016/j.biopsych.2010.04.029. View

Voorn P, Vanderschuren L, Groenewegen H, Robbins T, Pennartz C . Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci. 2004; 27(8):468-74. DOI: 10.1016/j.tins.2004.06.006. View

Krishnan K, McDonald W, Escalona P, Doraiswamy P, Na C, Husain M . Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Arch Gen Psychiatry. 1992; 49(7):553-7. DOI: 10.1001/archpsyc.1992.01820070047007. View

Heiman M, Schaefer A, Gong S, Peterson J, Day M, Ramsey K . A translational profiling approach for the molecular characterization of CNS cell types. Cell. 2008; 135(4):738-48. PMC: 2696821. DOI: 10.1016/j.cell.2008.10.028. View

Doyle J, Dougherty J, Heiman M, Schmidt E, Stevens T, Ma G . Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell. 2008; 135(4):749-62. PMC: 2763427. DOI: 10.1016/j.cell.2008.10.029. View

Drevets W, Price J, Furey M . Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008; 213(1-2):93-118. PMC: 2522333. DOI: 10.1007/s00429-008-0189-x. View

Mayberg H . Targeted electrode-based modulation of neural circuits for depression. J Clin Invest. 2009; 119(4):717-25. PMC: 2662569. DOI: 10.1172/JCI38454. View

Delgado M . Reward-related responses in the human striatum. Ann N Y Acad Sci. 2007; 1104:70-88. DOI: 10.1196/annals.1390.002. View

Gradin V, Kumar P, Waiter G, Ahearn T, Stickle C, Milders M . Expected value and prediction error abnormalities in depression and schizophrenia. Brain. 2011; 134(Pt 6):1751-64. DOI: 10.1093/brain/awr059. View

10.

Ressler K, Mayberg H . Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci. 2007; 10(9):1116-24. PMC: 2444035. DOI: 10.1038/nn1944. View

11.

Anisman H, Du L, Palkovits M, Faludi G, Kovacs G, Szontagh-Kishazi P . Serotonin receptor subtype and p11 mRNA expression in stress-relevant brain regions of suicide and control subjects. J Psychiatry Neurosci. 2008; 33(2):131-41. PMC: 2265306. View

12.

Krishnan V, Nestler E . The molecular neurobiology of depression. Nature. 2008; 455(7215):894-902. PMC: 2721780. DOI: 10.1038/nature07455. View

13.

Drevets W . Functional anatomical abnormalities in limbic and prefrontal cortical structures in major depression. Prog Brain Res. 2000; 126:413-31. DOI: 10.1016/S0079-6123(00)26027-5. View

14.

Mayberg H, Liotti M, Brannan S, McGinnis S, Mahurin R, Jerabek P . Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999; 156(5):675-82. DOI: 10.1176/ajp.156.5.675. View

15.

Arlotta P, Molyneaux B, Chen J, Inoue J, Kominami R, Macklis J . Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron. 2005; 45(2):207-21. DOI: 10.1016/j.neuron.2004.12.036. View

16.

Gong S, Yang X, Li C, Heintz N . Highly efficient modification of bacterial artificial chromosomes (BACs) using novel shuttle vectors containing the R6Kgamma origin of replication. Genome Res. 2002; 12(12):1992-8. PMC: 187570. DOI: 10.1101/gr.476202. View

17.

Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M . Alterations in 5-HT1B receptor function by p11 in depression-like states. Science. 2006; 311(5757):77-80. DOI: 10.1126/science.1117571. View

18.

Cryan J, Mombereau C, Vassout A . The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev. 2005; 29(4-5):571-625. DOI: 10.1016/j.neubiorev.2005.03.009. View

19.

Pizzagalli D, Holmes A, Dillon D, Goetz E, Birk J, Bogdan R . Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am J Psychiatry. 2009; 166(6):702-10. PMC: 2735451. DOI: 10.1176/appi.ajp.2008.08081201. View

20.

Covington 3rd H, Lobo M, Maze I, Vialou V, Hyman J, Zaman S . Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci. 2010; 30(48):16082-90. PMC: 3004756. DOI: 10.1523/JNEUROSCI.1731-10.2010. View