A pivotal role of GSK-3 in synaptic plasticity

Bradley, Clarrisa A.; Peineau, Stéphane; Taghibiglou, Changiz; Nicolas, Céline S.; Whitcomb, Daniel J.; Bortolotto, Zuner A.; Kaang, Bong‐Kiun; Cho, Kwangwook; Wang, Yu Tian; Collingridge, Graham L.

doi:10.3389/fnmol.2012.00013

Cited by 159 publications

(129 citation statements)

References 118 publications

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“…Figure 7 illustrates how a persistent block of GSK-3 would remove tonic inhibition from mTOR, potentially negating its physiological role in transient, activity-dependent dendritic protein translation. This is exemplified by late-phase LTP, which requires transient inhibition of LTD for stabilization of nascent synapses that otherwise would be lost through the process of GSK-3-mediated destabilization or synaptosis (Bradley et al, 2012). Clearly, in an effort to stabilize connectivity gains achieved with either single or repeat treatments with low dose ketamine, further studies will be necessary to determine the appropriate schedule for administering lithium or selective GSK-3 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Downstream of mTOR, the initiation of activity-dependent dendritic protein translation (Hoeffer and Klann, 2010) is seen to promote synthesis and insertion of synaptic proteins (eg, GluA1 and PSD95) into the postsynaptic density of dendritic spines (Li et al, 2010). At the synapse, inhibition of GSK-3 is shown to favor synaptic homeostasis by protecting spines from premature LTD-like deconsolidation (Bradley et al, 2012). As the model would predict, knock-in mice lacking serine sites for inhibitory phosphorylation of GSK-3 are more susceptible to chronic stress-induced depressive-like behaviors (Polter et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to mTORC1 signaling, the low-dose combination of ketamine and lithium increased inhibitory phosphorylation of GSK-3, which would diminish its inhibitory influence on mTOR ( Figure 7); this increase was transient, paralleling the transient activation of mTOR. Inhibition of GSK-3 may be critical in protecting nascent synapses from being lost through destabilization, as has been postulated for latephase LTP (Bradley et al, 2012). GSK-3b, which can act as a negative regulator of mTORC1 by phosphorylating and activating TSC2 (Zoncu, et al, 2011; Figure 7), is a major regulator of NMDA receptor-mediated long-term depression (LTD) (Collingridge et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Liu

Fuchikami

Dwyer

et al. 2013

Neuropsychopharmacol

221

162

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A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. Recent studies in medial prefrontal cortex (mPFC) show that the synaptogenic and antidepressant-like effects of a single standard dose of ketamine in rodents are dependent upon activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling pathway together with inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3), which relieves its inhibitory in influence on mTOR. Here, we found that the synaptogenic and antidepressant-like effects of a single otherwise subthreshold dose of ketamine were potentiated when given together with a single dose of lithium chloride (a nonselective GSK-3 inhibitor) or a preferential GSK-3b inhibitor; these effects included rapid activation of the mTORC1 signaling pathway, increased inhibitory phosphorylation of GSK-3b, increased synaptic spine density/ diameter, increased excitatory postsynaptic currents in mPFC layer V pyramidal neurons, and antidepressant responses that persist for up to 1 week in the forced-swim test model of depression. The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Liu

Fuchikami

Dwyer

et al. 2013

Neuropsychopharmacol

221

162

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“…These findings indicate that mGluR5 antagonist might be a good candidate for therapeutic application. In addition, GSK3 is a newly found signal protein that is important for synaptic plasticity, closely related to mGluR5 signaling and overexpressed in Fmr1 KO mice (Bradley et al, 2012;Guo et al, 2012;Liu et al, 2005;Min et al, 2009). However, the function of GSK3 in FXS is less investigated.…”

Section: Pharmacological Inhibition Of Mglur5 or Gsk3mentioning

confidence: 99%

Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Chen

Song

et al. 2014

Neuropsychopharmacol

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Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/ channels within the cingulate circuit and is typically detected in B75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.

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“…GSK-3 занимает важное место в ре-гуляции процессов нейропластичности и нейронального морфогенеза [18]. Одним из недавних открытий явля-ется участие GSK-3 в синаптической пластичности, необходимой для регуляции процессов памяти, обуче-ния [19,20,21].…”

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Tauopathy and cognitive impairment in experimental diabetes mellitus

et al. 2017

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Обучение и психосоциальные аспекты Education and psychosocial aspectТаупатии и когнитивные нарушения ау-протеин, ассоциированный с микротрубоч-ками центральной нервной системы (ЦНС), представляет собой белок цитоскелета, регули-рующий развитие нейронов и способствующий сборке и стабильности микротрубочек, которые являются важ-ными для транспорта везикул в ЦНС. В человеческом мозге семейство тау-белков представлено шестью изо-формами в диапазоне от 352 до 441 аминокислот, получен-ных из одного гена путем альтернативного сплайсинга [1]. Амино-концевой остаток тау-протеина (или «область проекции» микротрубочек) взаимодействует с плаз-матической мембраной. Карбоксиконцевая область характеризуется наличием 3 или 4 повторов, которые обе-спечивают свойства тау-белков для стабилизации микро-трубочек, способствуют их полимеризации. Эти функции негативно регулируются с помощью фосфорилирования в нескольких местах (и вокруг) связывающего домена ми-кротрубочек. Этот процесс может проходить с участием нескольких киназ [2,3]. Почти 20% от тау-белка фосфо-рилируется в физиологических условиях [4]. Внутрикле-точные агрегаты избыточно гиперфосфорилированного тау-белка характеризуют группу нейродегенеративных заболеваний под названием «таупатии» [5,6,7]. Все та-упатии делятся на спорадические нейродегенеративные заболевания (прогрессирующий надъядерный паралич, мультисистемная атрофия, деменция с тельцами Леви, болезнь Альцгеймера (БА) и др.) и ирритативные (болезнь Гентингтона, Вильсона-Коновалова, Фара и др.) [8].Патогенез таупатий включает накопление тау-белка в головном мозге и прогрессирующее нарушение ра-

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A pivotal role of GSK-3 in synaptic plasticity

Cited by 159 publications

References 118 publications

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

GSK-3 Inhibition Potentiates the Synaptogenic and Antidepressant-Like Effects of Subthreshold Doses of Ketamine

Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

Tauopathy and cognitive impairment in experimental diabetes mellitus

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