Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus

Amini, Aeen Ebrahim; Miyata, Tsukiko; Liu, Gang; Jin, Fuzi; Rubie, Elizabeth A.; Bradley, Clarrisa A.; Woodgett, James R.; Collingridge, Graham L.; Georgiou, John

doi:10.3389/fnmol.2022.852171

Cited by 3 publications

(4 citation statements)

References 54 publications

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“…GSK-3α also plays a differential role compared to the βisoform in brain plasticity, preserving the correct balance between long-term depression (LTD) and long-term potentiation (LTP) in mouse brain 11 and GSK-3α is required for LTD through transient anchoring in dendritic spines 12 and for limiting LTP. 13 The lethality of Gsk3b global knockout mice precludes determination of isoform-specific roles in knockout animal models. Conversely, genetic knockdown and knockout of GSK-3 in cell lines have offered insight into isoform-specific roles.…”

Section: ■ Introductionmentioning

confidence: 99%

“…This observation led to the discovery that GSK-3α is a suppressor of aging, slowing age-related pathologies in the heart, liver, small intestine, bones, and joints and suggesting that GSK-3α may have a distinct role in autophagy. GSK-3α also plays a differential role compared to the β-isoform in brain plasticity, preserving the correct balance between long-term depression (LTD) and long-term potentiation (LTP) in mouse brain and GSK-3α is required for LTD through transient anchoring in dendritic spines and for limiting LTP …”

Section: Introductionmentioning

confidence: 99%

“…GSK-3α also plays a differential role compared to the β-isoform in brain plasticity, preserving the correct balance between long-term depression (LTD) and long-term potentiation (LTP) in mouse brain 11 and GSK-3α is required for LTD through transient anchoring in dendritic spines 12 and for limiting LTP. 13 …”

Section: Introductionmentioning

confidence: 99%

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Interactomes of Glycogen Synthase Kinase-3 Isoforms

et al. 2023

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Functional differentiation of the two isoforms of the protein-serine/threonine kinase, glycogen synthase kinase-3 (GSK-3), is an unsettled area of research. The isoforms are highly similar in structure and are largely redundant, though there is also evidence for specific roles. Identification of isoform-specific protein interactors may elucidate the differences in function and provide insight into isoform-selective regulation. We therefore sought to identify novel GSK-3 interaction partners and to examine differences in the interactomes of the two isoforms using both affinity purification and proximity-dependent biotinylation (BioID) mass spectrometry methods. While the interactomes of the two isomers are highly similar in HEK293 cells, BioID in HeLa cells yielded a variety of preys that are preferentially associated with one of the two isoforms. DCP1B, which favored GSK-3α, and MISP, which favored GSK-3β, were evaluated for reciprocal interactions. The differences in interactions between isoforms may help in understanding the distinct functions and regulation of the two isoforms as well as offer avenues for the development of isoform-specific strategies.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Interactomes of Glycogen Synthase Kinase-3 Isoforms

et al. 2023

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“…CDKL1-4 mRNA are expressed at much lower levels than CDKL5 in mouse and human brain ( http://mouse.brain-map.org ). Of these kinases, only GSK3α ( Shahab et al, 2014 ; Ebrahim Amini et al, 2022 ) and GSK3β Peineau et al, 2008 have been linked to brain synaptic function.…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Castano,

Silvestre,

Wells

et al. 2023

eLife

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Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD have indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3b, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3b activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3b activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3b. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces post-synaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated, key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity and human neuropathology.

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Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome

Alexander,

Vazquez-Ramirez,

Lin

et al. 2024

EMBO Mol Med

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CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain β-catenin, β-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3α,β that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome.

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Specific Role for GSK3α in Limiting Long-Term Potentiation in CA1 Pyramidal Neurons of Adult Mouse Hippocampus

Cited by 3 publications

References 54 publications

Interactomes of Glycogen Synthase Kinase-3 Isoforms

Interactomes of Glycogen Synthase Kinase-3 Isoforms

Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology

Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome

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