Light and Electron Microscopy Study of Glycogen Synthase Kinase-3β in the Mouse Brain

Glycogen synthase kinase-3β (GSK3β) is highly abundant in the brain. Various biochemical analyses have indicated that GSK3β is localized to different intracellular compartments within brain cells. However, ultrastructural visualization of this kinase in various brain regions and in different brain cell types has not been reported. The goal of the present study was to examine GSK3β distribution and subcellular localization in the brain using immunohistochemistry combined with light and electron microscopy. Initial examination by light microscopy revealed that GSK3β is expressed in brain neurons and their dendrites throughout all the rostrocaudal extent of the adult mouse brain, and abundant GSK3β staining was found in the cortex, hippocampus, basal ganglia, the cerebellum, and some brainstem nuclei. Examination by transmission electron microscopy revealed highly specific subcellular localization of GSK3β in neurons and astrocytes. At the subcellular level, GSK3β was present in the rough endoplasmic reticulum, free ribosomes, and mitochondria of neurons and astrocytes. In addition GSK3β was also present in dendrites and dendritic spines, with some postsynaptic densities clearly labeled for GSK3β. Phosphorylation at serine-9 of GSK3β (pSer9GSK3β) reduces kinase activity. pSer9GSK3β labeling was present in all brain regions, but the pattern of staining was clearly different, with an abundance of labeling in microglia cells in all regions analyzed and much less neuronal staining in the subcortical regions. At the subcellular level pSer9GSK3β labeling was located in the endoplasmic reticulum, free ribosomes and in some of the nuclei. Overall, in normal brains constitutively active GSK3β is predominantly present in neurons while pSer9GSK3β is more evident in resting microglia cells. This visual assessment of GSK3β localization within the subcellular structures of various brain cells may help in understanding the diverse role of GSK3β signaling in the brain.

• Publication year

  2010

• Venue

  PLoS ONE

• Publication date

  2010-01-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1371/journal.pone.0008911PMID 20111716PMCID 2811740
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• GSK-3β Gene Expression in Human Postmortem Brain: Regional Distribution, Effects of Age and Suicide

  2009cited by this paper
• Glycogen synthase kinase-3 regulates microglial migration, inflammation, and inflammation-induced neurotoxicity.

  2009cited by this paper
• Involvment of Cytosolic and Mitochondrial GSK-3β in Mitochondrial Dysfunction and Neuronal Cell Death of MPTP/MPP+-Treated Neurons

  2009cited by this paper
• The role of GSK‐3 in synaptic plasticity

  2008cited by this paper
• The role of glycogen synthase kinase 3 in the early stages of Alzheimers’ disease

  2008cited by this paper
• Dopamine Inhibits Mitochondrial Motility in Hippocampal Neurons

  2008cited by this paper
• Unregulated mitochondrial GSK3β activity results in NADH:Ubiquinone oxidoreductase deficiency

  2008cited by this paper
• Differential Regulation of STAT Family Members by Glycogen Synthase Kinase-3*

  2008cited by this paper
• Glycogen synthase kinase‐3 inhibition is integral to long‐term potentiation

  2007cited by this paper
• Resolution of the Nuclear Localization Mechanism of Glycogen Synthase Kinase-3

  2007cited by this paper
• LTP inhibits LTD in the hippocampus via regulation of GSK3beta.

  2007cited by this paper
• Inhibition of GSK-3β mediates expression of MMP-9 through ERK1/2 activation and translocation of NF-κB in rat primary astrocyte

  2007cited by this paper
• GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder.

  2007cited by this paper
• Activation of Glycogen Synthase Kinase-3 Inhibits Long-Term Potentiation with Synapse-Associated Impairments

  2007cited by this paper
• Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

  2007cited by this paper
• Inhibition of GSK-3beta mediates expression of MMP-9 through ERK1/2 activation and translocation of NF-kappaB in rat primary astrocyte.

  2007cited by this paper
• Regulation of protein synthesis by insulin.

  2006cited by this paper
• In vivo regulation of GSK3 phosphorylation by cholinergic and NMDA receptors.

  2006cited by this paper
• Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions.

  2006cited by this paper
• Age-related changes in glycogen synthase kinase 3beta (GSK3beta) immunoreactivity in the central nervous system of rats.

  2006cited by this paper
• Glycogen synthase kinase 3beta modulates synphilin-1 ubiquitylation and cellular inclusion formation by SIAH: implications for proteasomal function and Lewy body formation.

  2005cited by this paper
• Antipsychotics alter the protein expression levels of beta-catenin and GSK-3 in the rat medial prefrontal cortex and striatum.

  2005cited by this paper
• Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia

  2004cited by this paper
• Glycogen synthase kinase 3beta-mediated apoptosis of primary cortical astrocytes involves inhibition of nuclear factor kappaB signaling.

  2003cited by this paper
• Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3‐kinase activation

  2003cited by this paper
• Glycogen synthase kinase-3&bgr; is highly activated in nuclei and mitochondria

  2003cited by this paper
• In vivo activation and nuclear translocation of phosphorylated glycogen synthase kinase‐3β in neuronal apoptosis: links to tau phosphorylation

  2002cited by this paper
• The active form of glycogen synthase kinase-3β is associated with granulovacuolar degeneration in neurons in Alzheimer's disease

  2002cited by this paper
• Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration

  2002cited by this paper
• Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation*

  2002cited by this paper
• Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium.

  2001cited by this paper
• Proapoptotic Stimuli Induce Nuclear Accumulation of Glycogen Synthase Kinase-3β*

  2001cited by this paper
• Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3β and attenuated by lithium

  2001cited by this paper
• Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A.

  2000cited by this paper
• Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients.

  2000cited by this paper
• Distribution of tau protein kinase I/glycogen synthase kinase-3beta, phosphatases 2A and 2B, and phosphorylated tau in the developing rat brain.

  2000cited by this paper
• Distribution of Active Glycogen Synthase Kinase 3β (GSK-3β) in Brains Staged for Alzheimer Disease Neurofibrillary Changes

  1999cited by this paper
• Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes.

  1999cited by this paper
• Anti-bipolar therapy: mechanism of action of lithium

  1999cited by this paper
• A GSK3‐binding peptide from FRAT1 selectively inhibits the GSK3‐catalysed phosphorylation of Axin and β‐catenin

  1999cited by this paper
• Developmental expression and localization of glycogen synthase kinase-3beta in rat brain.

  1999cited by this paper
• GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis.

  1998cited by this paper
• Distribution, Levels, and Activity of Glycogen Synthase Kinase‐3 in the Alzheimer Disease Brain

  1997influential reference
• Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain.

  1996cited by this paper
• A molecular mechanism for the effect of lithium on development.

  1996cited by this paper
• Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells.

  1996cited by this paper
• Expression and characterization of glycogen synthase kinase-3 mutants and their effect on glycogen synthase activity in intact cells.

  1996cited by this paper
• Immunocytochemistry of tau phosphoserine 413 and tau protein kinase I in Alzheimer pathology.

  1996cited by this paper
• Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B

  1995cited by this paper
• Different localization of tau protein kinase I/glycogen synthase kinase-3 beta from glycogen synthase kinase-3 alpha in cerebellum mitochondria.

  1995cited by this paper
• Regulation of protein synthesis by insulin.

  1994cited by this paper
• Localization and Developmental Changes of τ Protein Kinase I/Glycogen Synthase Kinase‐3β in Rat Brain

  1994cited by this paper
• Modulation of the glycogen synthase kinase‐3 family by tyrosine phosphorylation.

  1993cited by this paper
• Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling.

  1993cited by this paper
• Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase.

  1992cited by this paper
• Glycogen synthase kinase‐3 and the Alzheimer‐like state of microtubule‐associated protein tau

  1992cited by this paper
• Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes.

  1992cited by this paper
• Molecular cloning and expression of glycogen synthase kinase‐3/factor A.

  1990cited by this paper
• Purification of glycogen synthase kinase 3 from rabbit skeletal muscle. Copurification with the activating factor (FA) of the (Mg-ATP) dependent protein phosphatase.

  1981cited by this paper
• Glycogen Synthase Kinase 3 (cid:2) -Mediated Apoptosis of Primary Cortical Astrocytes Involves Inhibition of Nuclear Factor (cid:3) B Signaling

  year unknowncited by this paper
• Glycogen Synthase Kinase-3 (cid:1) Inhibitors Prevent Cellular Polyglutamine Toxicity Caused by the Huntington’s Disease Mutation*

  year unknowncited by this paper

• A review of developments in glycogen synthase Kinase-3 regulators over the past 10 years.

  2025cites this paper
• Identification of Flavonoids-based HITS to Inhibit GSK3β Activity: An In Silico and In Vitro Analysis

  2024cites this paper
• GSK3: A potential target and pending issues for treatment of Alzheimer's disease

  2024cites this paper
• Understanding Glycogen Synthase Kinase-3: A Novel Avenue for Alzheimer’s Disease

  2023cites this paper
• Novel 18F-Labeled Isonicotinamide-Based Radioligands for Positron Emission Tomography Imaging of Glycogen Synthase Kinase-3β.

  2021cites this paper
• Neuroprotective Effects of Thiamine and Precursors with Higher Bioavailability: Focus on Benfotiamine and Dibenzoylthiamine

  2021cites this paper
• Increased glutamate transmission onto dorsal striatum spiny projection neurons in Pink1 knockout rats.

  2020cites this paper
• Regulation of GSK3β by Ser389 Phosphorylation During Neural Development

  2020cites this paper
• Control of neuronal excitability by GSK-3beta: epilepsy and beyond.

  2020cites this paper
• CRISPR-Cas9-Mediated Intersectional Knockout of Glycogen Synthase Kinase 3β in D2 Receptor–Expressing Medial Prefrontal Cortex Neurons Reveals Contributions to Emotional Regulation

  2020cites this paper
• Regulation of GSK3β by Ser389 Phosphorylation During Neural Development

  2020cites this paper
• Involvement of PI3K/Akt/GSK-3β signaling pathway in the antidepressant-like and neuroprotective effects of Morus nigra and its major phenolic, syringic acid.

  2019cites this paper
• CRISPR/Cas9 mediated intersectional knockout of GSK3β in D2 receptor expressing mPFC neurons reveals contributions to emotional regulation

  2019cites this paper
• GSK-3β at the Intersection of Neuronal Plasticity and Neurodegeneration

  2019cites this paper
• Astroglial 5-HT2B receptor in mood disorders

  2018cites this paper
• Isoprenoids and tau pathology in sporadic Alzheimer's disease.

  2018cites this paper
• Regulation of Glycogen Content in Astrocytes via Cav-1/PTEN/AKT/GSK-3β Pathway by Three Anti-bipolar Drugs

  2018cites this paper
• A novel GLP‐1/GIP/Gcg triagonist reduces cognitive deficits and pathology in the 3xTg mouse model of Alzheimer's disease

  2018cites this paper
• Mental Illnesses-Associated Fxr1 and Its Negative Regulator Gsk3β Are Modulators of Anxiety and Glutamatergic Neurotransmission

  2018cites this paper
• Chapter 9 – The mGluR Theory of Fragile X: From Mice to Men

  2017cites this paper
• Bi-phasic regulation of glycogen content in astrocytes via Cav-1/PTEN/PI3K/AKT/GSK-3β pathway by fluoxetine

  2017cites this paper
• Folic Acid Protects Against Glutamate-Induced Excitotoxicity in Hippocampal Slices Through a Mechanism that Implicates Inhibition of GSK-3β and iNOS

  2017cites this paper
• SB203580 reverses memory deficits and depression-like behavior induced by microinjection of Aβ1–42 into hippocampus of mice

  2017cites this paper
• Prenatal Alcohol Exposure Leads to Enhanced Serine 9 Phosphorylation of Glycogen Synthase Kinase‐3&bgr; (GSK‐3&bgr;) in the Hippocampal Dentate Gyrus of Adult Mouse

  2017cites this paper
• GSK3β inhibition protects the immature brain from hypoxic-ischaemic insult via reduced STAT3 signalling.

  2016cites this paper
• Activation of AKT1/GSK-3β/β-Catenin–TRIM11/Survivin Pathway by Novel GSK-3β Inhibitor Promotes Neuron Cell Survival: Study in Differentiated SH-SY5Y Cells in OGD Model

  2016cites this paper
• Tideglusib, a chemical inhibitor of GSK3β, attenuates hypoxic-ischemic brain injury in neonatal mice.

  2016cites this paper
• Idebenone protects against oxidized low density lipoprotein induced mitochondrial dysfunction in vascular endothelial cells via GSK3β/β-catenin signalling pathways.

  2015cites this paper
• Reelin expression in brain endothelial cells: an electron microscopy study

  2015cites this paper
• Learning ability is a key outcome determinant of GSK-3 inhibition on visuospatial memory in rats

  2015cites this paper
• LEPTIN RESISTANCE INDUCED OBESITY AND DIABETES PROMOTE NEUROPATHOLOGICAL CHANGES IN THE AGING BRAIN

  2014cites this paper
• Neurotoxic Vulnerability Underlying Schizophrenia Spectrum Disorders

  2014cites this paper
• The glial perspective of autism spectrum disorders.

  2014cites this paper
• GSK3 in Alzheimer's Disease: Mind the Isoforms

  2014cites this paper
• Interleukin-18 directly protects cortical neurons by activating PI3K/AKT/NF-κB/CREB pathways.

  2014cites this paper
• Glycogen synthase kinase‐3β (GSK3β) expression in a mouse model of Alzheimer's disease: A light and electron microscopy study

  2013influential citation
• The Effects of Disc1 on Neurodevelopment in the Mouse

  2013cites this paper
• Possible Role of the Glycogen Synthase Kinase-3 Signaling Pathway in Trimethyltin-Induced Hippocampal Neurodegeneration in Mice

  2013cites this paper
• ACUTE ETHANOL EXPOSURE INCREASES THE ACTIVITY OF MITOCHONDRIA-ASSOCIATED GLYCOGEN SYNTHASE KINASE-3 BETA (GSK-3Β): ROLE IN PHOSPHORYLATION OF MITOCHONDRIAL PROTEINS

  2013cites this paper
• Neurological characterization of mice deficient in GSK3α highlight pleiotropic physiological functions in cognition and pathological activity as Tau kinase

  2013cites this paper
• GSK-3β Polymorphism Discriminates Bipolar Disorder and Schizophrenia: A Systematic Meta-Analysis

  2013cites this paper
• Unlocking mechanisms in interleukin-1β-induced changes in hippocampal neurogenesis—a role for GSK-3β and TLX

  2012cites this paper
• Glycogen Synthase Kinase-3 in Neurological Diseases

  2012cites this paper
• Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice.

  2012cites this paper
• Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice.

  2011cites this paper
• Phiel et al. reply

  2011cites this paper
• GSK-3: Functional Insights from Cell Biology and Animal Models

  2011cites this paper
• GSK-3α/β kinases and amyloid production in vivo

  2011cites this paper
• Genetic and pharmacological evidence for schizophrenia‐related Disc1 interaction with GSK‐3

  2011cites this paper
• Glycogen Synthase Kinase-3 is an Intermediate Modulator of Serotonin Neurotransmission

  2011cites this paper
• GSK3 and Alzheimer’s Disease: Facts and Fiction…

  2011cites this paper
• REGULATION OF DOPAMINERGIC AND IMMUNE MARKERS IN THE RAT STRIATUM: EXPLORING THE MODULATORY EFFECTS OF D2R ANTAGONISM, SERT INHIBITION, ENVIRONMENTAL ENRICHMENT AND MICROGLIAL ACTIVATION

  2011cites this paper
• GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration

  2011cites this paper