Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

Nataliya Gorinski; Monika Bijata; Sonal Prasad; Alexander Wirth; Dalia Abdel Galil; Andre Zeug; Darla Bazovkina; Elena Kondaurova; Elizabeth Kulikova; Tatiana Ilchibaeva; Monika Zareba-Koziol; Francesco Papaleo; Diego Scheggia; Gaga Kochlamazashvili; Alexander Dityatev; Ian Smyth; Adam Krzystyniak; Jakub Wlodarczyk; Diethelm W. Richter; Tatyana Strekalova; Stephan Sigrist; Claudia Bang; Lisa Hobuss; Jan Fiedler; Thomas Thum; Vladimir S. Naumenko; Ghanshyam Pandey; Evgeni Ponimaskin

doi:10.1038/s41467-019-11876-5

Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

Nataliya Gorinski
, Monika Bijata
, Sonal Prasad
, Alexander Wirth
, Dalia Abdel Galil
, Andre Zeug
, Darla Bazovkina
, Elena Kondaurova
, Elizabeth Kulikova
, Tatiana Ilchibaeva
, Monika Zareba-Koziol
, Francesco Papaleo
, Diego Scheggia
, Gaga Kochlamazashvili
, Alexander Dityatev
, Ian Smyth
, Adam Krzystyniak
, Jakub Wlodarczyk
, Diethelm W. Richter
, Tatyana Strekalova

Stephan Sigrist, Claudia Bang, Lisa Hobuss, Jan Fiedler, Thomas Thum, Vladimir S. Naumenko^*, Ghanshyam Pandey^*, Evgeni Ponimaskin^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.

Original language	English
Article number	3924
Number of pages	14
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11876-5
Publication status	Published - 2 Sept 2019

Keywords

PREFRONTAL CORTEX
MAJOR DEPRESSION
5-HYDROXYTRYPTAMINE(1A) RECEPTOR
PROTEIN PALMITOYLATION
CODING REGION
MICE LACKING
1A BINDING
STRESS
EXPRESSION
MICRORNAS

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Gorinski, N., Bijata, M., Prasad, S., Wirth, A., Galil, D. A., Zeug, A., Bazovkina, D., Kondaurova, E., Kulikova, E., Ilchibaeva, T., Zareba-Koziol, M., Papaleo, F., Scheggia, D., Kochlamazashvili, G., Dityatev, A., Smyth, I., Krzystyniak, A., Wlodarczyk, J., Richter, D. W., ... Ponimaskin, E. (2019). Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors. Nature Communications, 10(1), Article 3924. https://doi.org/10.1038/s41467-019-11876-5

@article{b0a160d232fc4278a017651c3dc6b42e,

title = "Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors",

abstract = "The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.",

keywords = "PREFRONTAL CORTEX, MAJOR DEPRESSION, 5-HYDROXYTRYPTAMINE(1A) RECEPTOR, PROTEIN PALMITOYLATION, CODING REGION, MICE LACKING, 1A BINDING, STRESS, EXPRESSION, MICRORNAS",

author = "Nataliya Gorinski and Monika Bijata and Sonal Prasad and Alexander Wirth and Galil, \{Dalia Abdel\} and Andre Zeug and Darla Bazovkina and Elena Kondaurova and Elizabeth Kulikova and Tatiana Ilchibaeva and Monika Zareba-Koziol and Francesco Papaleo and Diego Scheggia and Gaga Kochlamazashvili and Alexander Dityatev and Ian Smyth and Adam Krzystyniak and Jakub Wlodarczyk and Richter, \{Diethelm W.\} and Tatyana Strekalova and Stephan Sigrist and Claudia Bang and Lisa Hobuss and Jan Fiedler and Thomas Thum and Naumenko, \{Vladimir S.\} and Ghanshyam Pandey and Evgeni Ponimaskin",

note = "Funding Information: We thank Dr. Nicholas Davis for his help in establishing the ABE assay and Dr. Masaki Fukata for providing ZDHHC clones. We thank Elena Zakharova and Viktoria Ravkina for technical support and Dr. Christo Goridis and Dr. Martina Muehlenhoff for providing anti-NCAM antibodies. This study was supported by the Deutsche For-schungsgemeinschaft (DFG) grant PO732 to E.P.; by the Basic Research project \#0324–2019–0041 and Russian Scientific Foundation (grant No 19-15-00025) to V.S.N.; and by “5–100” Russian Academic Excellence Project, NARSAD and the Brain and Behavior Research Fund, Young Investigator Award to T.S. T.T. was supported by a Consolidator ERC grant from the European Union, and T.T. and E.P. were supported by the REBIRTH Excellence cluster. J.W., A.K., and M.Z. acknowledge the National Science Centre grants: UMO-2017/26/E/NZ4/00637. M.B. has been partially supported by the Polish Ministry of Science (1342/1/MOB/IV/15/2016/0). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = sep,

day = "2",

doi = "10.1038/s41467-019-11876-5",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Gorinski, N, Bijata, M, Prasad, S, Wirth, A, Galil, DA, Zeug, A, Bazovkina, D, Kondaurova, E, Kulikova, E, Ilchibaeva, T, Zareba-Koziol, M, Papaleo, F, Scheggia, D, Kochlamazashvili, G, Dityatev, A, Smyth, I, Krzystyniak, A, Wlodarczyk, J, Richter, DW, Strekalova, T, Sigrist, S, Bang, C, Hobuss, L, Fiedler, J, Thum, T, Naumenko, VS, Pandey, G & Ponimaskin, E 2019, 'Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors', Nature Communications, vol. 10, no. 1, 3924. https://doi.org/10.1038/s41467-019-11876-5

TY - JOUR

T1 - Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

AU - Gorinski, Nataliya

AU - Bijata, Monika

AU - Prasad, Sonal

AU - Wirth, Alexander

AU - Galil, Dalia Abdel

AU - Zeug, Andre

AU - Bazovkina, Darla

AU - Kondaurova, Elena

AU - Kulikova, Elizabeth

AU - Ilchibaeva, Tatiana

AU - Zareba-Koziol, Monika

AU - Papaleo, Francesco

AU - Scheggia, Diego

AU - Kochlamazashvili, Gaga

AU - Dityatev, Alexander

AU - Smyth, Ian

AU - Krzystyniak, Adam

AU - Wlodarczyk, Jakub

AU - Richter, Diethelm W.

AU - Strekalova, Tatyana

AU - Sigrist, Stephan

AU - Bang, Claudia

AU - Hobuss, Lisa

AU - Fiedler, Jan

AU - Thum, Thomas

AU - Naumenko, Vladimir S.

AU - Pandey, Ghanshyam

AU - Ponimaskin, Evgeni

N1 - Funding Information: We thank Dr. Nicholas Davis for his help in establishing the ABE assay and Dr. Masaki Fukata for providing ZDHHC clones. We thank Elena Zakharova and Viktoria Ravkina for technical support and Dr. Christo Goridis and Dr. Martina Muehlenhoff for providing anti-NCAM antibodies. This study was supported by the Deutsche For-schungsgemeinschaft (DFG) grant PO732 to E.P.; by the Basic Research project #0324–2019–0041 and Russian Scientific Foundation (grant No 19-15-00025) to V.S.N.; and by “5–100” Russian Academic Excellence Project, NARSAD and the Brain and Behavior Research Fund, Young Investigator Award to T.S. T.T. was supported by a Consolidator ERC grant from the European Union, and T.T. and E.P. were supported by the REBIRTH Excellence cluster. J.W., A.K., and M.Z. acknowledge the National Science Centre grants: UMO-2017/26/E/NZ4/00637. M.B. has been partially supported by the Polish Ministry of Science (1342/1/MOB/IV/15/2016/0). Publisher Copyright: © 2019, The Author(s).

PY - 2019/9/2

Y1 - 2019/9/2

N2 - The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.

AB - The serotonergic system and in particular serotonin 1A receptor (5-HT1AR) are implicated in major depressive disorder (MDD). Here we demonstrated that 5-HT1AR is palmitoylated in human and rodent brains, and identified ZDHHC21 as a major palmitoyl acyltransferase, whose depletion reduced palmitoylation and consequently signaling functions of 5-HT1AR. Two rodent models for depression-like behavior show reduced brain ZDHHC21 expression and attenuated 5-HT1AR palmitoylation. Moreover, selective knock-down of ZDHHC21 in the murine forebrain induced depression-like behavior. We also identified the microRNA miR-30e as a negative regulator of Zdhhc21 expression. Through analysis of the post-mortem brain samples in individuals with MDD that died by suicide we find that miR-30e expression is increased, while ZDHHC21 expression, as well as palmitoylation of 5-HT1AR, are reduced within the prefrontal cortex. Our study suggests that downregulation of 5-HT1AR palmitoylation is a mechanism involved in depression, making the restoration of 5-HT1AR palmitoylation a promising clinical strategy for the treatment of MDD.

KW - PREFRONTAL CORTEX

KW - MAJOR DEPRESSION

KW - 5-HYDROXYTRYPTAMINE(1A) RECEPTOR

KW - PROTEIN PALMITOYLATION

KW - CODING REGION

KW - MICE LACKING

KW - 1A BINDING

KW - STRESS

KW - EXPRESSION

KW - MICRORNAS

U2 - 10.1038/s41467-019-11876-5

DO - 10.1038/s41467-019-11876-5

M3 - Article

C2 - 31477731

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3924

ER -

Attenuated palmitoylation of serotonin receptor 5-HT1A affects receptor function and contributes to depression-like behaviors

Abstract

Keywords

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