In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain

Xiaohua Li, Wawa Zhu, Myoung Sun Roh, Ari B. Friedman, Kelley Rosborough, Richard S Jope

Research output: Contribution to journalArticle

241 Citations (Scopus)

Abstract

The goal of this study was to determine if serotonergic activity, which is impaired in depression, regulates the phosphorylation of glycogen synthase kinase-3β (GSK3β) in mouse brain in vivo. GSK3β is inhibited by phosphorylation on serine-9 and is a target of the mood stabilizer lithium. Following administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho-Ser9-GSK3β were 300-400% of control levels in the prefrontal cortex, hippocampus, and striatum. Treatment with monoamine reuptake inhibitors fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3β. Using receptor selective agonists and antagonists, 5HT1A receptors were found to mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3β levels. This indicates that serotonergic regulation of the phosphorylation of GSK3β is achieved by a balance between the opposing actions of these 5HT receptor subtypes. These findings demonstrate for the first time that serotonergic activity regulates the phosphorylation of GSK3β and show that this regulation occurs in mammalian brain in vivo. These results raise the possibility that impaired inhibitory control of GSK3β may occur in conditions where serotonergic activity is dysregulated, such as in mood disorders.

Original languageEnglish
Pages (from-to)1426-1431
Number of pages6
JournalNeuropsychopharmacology
Volume29
Issue number8
DOIs
StatePublished - Aug 1 2004
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Brain
Phosphorylation
Clorgyline
Fenfluramine
Imipramine
Fluoxetine
Prefrontal Cortex
Mood Disorders
Lithium
Serine
Hippocampus
Serotonin
Depression

Keywords

  • 5HT1A receptor
  • 5HT2 receptor
  • Depression
  • Glycogen synthase kinase-3β
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology

Cite this

In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain. / Li, Xiaohua; Zhu, Wawa; Roh, Myoung Sun; Friedman, Ari B.; Rosborough, Kelley; Jope, Richard S.

In: Neuropsychopharmacology, Vol. 29, No. 8, 01.08.2004, p. 1426-1431.

Research output: Contribution to journalArticle

Li, Xiaohua ; Zhu, Wawa ; Roh, Myoung Sun ; Friedman, Ari B. ; Rosborough, Kelley ; Jope, Richard S. / In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain. In: Neuropsychopharmacology. 2004 ; Vol. 29, No. 8. pp. 1426-1431.
@article{f9e7768da797406faf03feb124f3c0f0,
title = "In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain",
abstract = "The goal of this study was to determine if serotonergic activity, which is impaired in depression, regulates the phosphorylation of glycogen synthase kinase-3β (GSK3β) in mouse brain in vivo. GSK3β is inhibited by phosphorylation on serine-9 and is a target of the mood stabilizer lithium. Following administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho-Ser9-GSK3β were 300-400{\%} of control levels in the prefrontal cortex, hippocampus, and striatum. Treatment with monoamine reuptake inhibitors fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3β. Using receptor selective agonists and antagonists, 5HT1A receptors were found to mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3β levels. This indicates that serotonergic regulation of the phosphorylation of GSK3β is achieved by a balance between the opposing actions of these 5HT receptor subtypes. These findings demonstrate for the first time that serotonergic activity regulates the phosphorylation of GSK3β and show that this regulation occurs in mammalian brain in vivo. These results raise the possibility that impaired inhibitory control of GSK3β may occur in conditions where serotonergic activity is dysregulated, such as in mood disorders.",
keywords = "5HT1A receptor, 5HT2 receptor, Depression, Glycogen synthase kinase-3β, Serotonin",
author = "Xiaohua Li and Wawa Zhu and Roh, {Myoung Sun} and Friedman, {Ari B.} and Kelley Rosborough and Jope, {Richard S}",
year = "2004",
month = "8",
day = "1",
doi = "10.1038/sj.npp.1300439",
language = "English",
volume = "29",
pages = "1426--1431",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

T1 - In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain

AU - Li, Xiaohua

AU - Zhu, Wawa

AU - Roh, Myoung Sun

AU - Friedman, Ari B.

AU - Rosborough, Kelley

AU - Jope, Richard S

PY - 2004/8/1

Y1 - 2004/8/1

N2 - The goal of this study was to determine if serotonergic activity, which is impaired in depression, regulates the phosphorylation of glycogen synthase kinase-3β (GSK3β) in mouse brain in vivo. GSK3β is inhibited by phosphorylation on serine-9 and is a target of the mood stabilizer lithium. Following administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho-Ser9-GSK3β were 300-400% of control levels in the prefrontal cortex, hippocampus, and striatum. Treatment with monoamine reuptake inhibitors fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3β. Using receptor selective agonists and antagonists, 5HT1A receptors were found to mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3β levels. This indicates that serotonergic regulation of the phosphorylation of GSK3β is achieved by a balance between the opposing actions of these 5HT receptor subtypes. These findings demonstrate for the first time that serotonergic activity regulates the phosphorylation of GSK3β and show that this regulation occurs in mammalian brain in vivo. These results raise the possibility that impaired inhibitory control of GSK3β may occur in conditions where serotonergic activity is dysregulated, such as in mood disorders.

AB - The goal of this study was to determine if serotonergic activity, which is impaired in depression, regulates the phosphorylation of glycogen synthase kinase-3β (GSK3β) in mouse brain in vivo. GSK3β is inhibited by phosphorylation on serine-9 and is a target of the mood stabilizer lithium. Following administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho-Ser9-GSK3β were 300-400% of control levels in the prefrontal cortex, hippocampus, and striatum. Treatment with monoamine reuptake inhibitors fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3β. Using receptor selective agonists and antagonists, 5HT1A receptors were found to mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3β levels. This indicates that serotonergic regulation of the phosphorylation of GSK3β is achieved by a balance between the opposing actions of these 5HT receptor subtypes. These findings demonstrate for the first time that serotonergic activity regulates the phosphorylation of GSK3β and show that this regulation occurs in mammalian brain in vivo. These results raise the possibility that impaired inhibitory control of GSK3β may occur in conditions where serotonergic activity is dysregulated, such as in mood disorders.

KW - 5HT1A receptor

KW - 5HT2 receptor

KW - Depression

KW - Glycogen synthase kinase-3β

KW - Serotonin

UR - http://www.scopus.com/inward/record.url?scp=3242761438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3242761438&partnerID=8YFLogxK

U2 - 10.1038/sj.npp.1300439

DO - 10.1038/sj.npp.1300439

M3 - Article

VL - 29

SP - 1426

EP - 1431

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 8

ER -