Activation of glycogen synthase kinase-3 inhibits LongTerm Potentiation with synapse-associated impairments
ABSTRACT Activation of glycogen synthase kinase-3 (GSK-3) can cause memory deficits as seen in Alzheimer's disease, the most common age-associated dementia, but the mechanism is not understood. Here, we found that activation of GSK-3 by wortmannin or transient overexpression of wild-type GSK-3beta could suppress the induction of long-term potentiation (LTP) in rat hippocampus, whereas simultaneous inhibition of GSK-3 by lithium or SB216763 or transient expression of a dominant-negative GSK-3beta mutant (dnGSK-3beta) preserved the LTP. After high-frequency stimulation (HFS), the presynaptic release of glutamate and the expression/clustering of synapsin I, a synaptic vesicle protein playing an important role in neurotransmitter release, decreased markedly after upregulation of GSK-3. In vitro studies further demonstrated that GSK-3 inhibited the expression of SynI independent of HFS. In postsynaptic level, the expression of PSD93 and NR2A/B proteins decreased significantly when GSK-3 was activated. The LTP-associated synapse impairments including less presynaptic active zone, thinner postsynaptic density, and broader synaptic cleft were also prominent in the hippocampal slices after HFS with activation of GSK-3. These synaptic impairments were attenuated when GSK-3 was simultaneously inhibited by LiCl or SB216763 or transient expression of dnGSK-3. We conclude that upregulation of GSK-3 impairs the synaptic plasticity both functionally and structurally, which may underlie the GSK-3-involved memory deficits.
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ABSTRACT: Bipolar disorder is associated with impaired decision-making. Little is known about how treatment, especially lithium, influences decision-making abilities in bipolar patients when euthymic. We aimed at testing for an association between lithium medication and decision-making performance in remitted bipolar patients. Decision-making was measured using the Iowa Gambling Task in 3 groups of subjects: 34 and 56 euthymic outpatients with bipolar disorder, treated with lithium (monotherapy and lithium combined with anticonvulsant or antipsychotic) and without lithium (anticonvulsant, antipsychotic and combination treatment), respectively, and 152 matched healthy controls. Performance was compared between the 3 groups. In the 90 euthymic patients, the relationship between different sociodemographic and clinical variables and decision-making was assessed by stepwise multivariate regression analysis. Euthymic patients with lithium (p=0.007) and healthy controls (p=0.001) selected significantly more cards from the safe decks than euthymic patients without lithium, with no significant difference between euthymic patients with lithium and healthy controls (p=0.9). In the 90 euthymic patients, the stepwise linear multivariate regression revealed that decision-making was significantly predicted (p<0.001) by lithium dose, level of education and no family history of bipolar disorder (all p≤0.01). Because medication was not randomized, it was not possible to discriminate the effect of different medications. Lithium medication might be associated with better decision-making in remitted bipolar patients. A randomized trial is required to test for the hypothesis that lithium, but not other mood stabilizers, may specifically improve decision-making abilities in bipolar disorder. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 03/2015; 25(6). DOI:10.1016/j.euroneuro.2015.03.003 · 5.40 Impact Factor
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ABSTRACT: The PI3K-dependent activation of AKT results in the inhibition of GSK3β in most signaling pathways. These kinases regulate multiple neuronal processes including the control of synapse number as shown for Drosophila and rodents. Alzheimer disease's patients exhibit high levels of circulating GSK3β and, consequently, pharmacological strategies based on GSK3β antagonists have been designed. The approach, however, has yielded inconclusive results so far. Here, we carried out a comparative study in Drosophila and rats addressing the role of GSK3β in synaptogenesis. In flies, the genetic inhibition of the shaggy-encoded GSK3β increases the number of synapses, while its upregulation leads to synapse loss. Likewise, in three weeks cultured rat hippocampal neurons, the pharmacological inhibition of GSK3β increases synapse density and Synapsin expression. However, experiments on younger cultures (12 days) yielded an opposite effect, a reduction of synapse density. This unexpected finding seems to unveil an age- and dosage-dependent differential response of mammalian neurons to the stimulation/inhibition of GSK3β, a feature that must be considered in the context of human adult neurogenesis and pharmacological treatments for Alzheimer's disease based on GSK3β antagonists.PLoS ONE 03/2015; 10(3):e0118475. DOI:10.1371/journal.pone.0118475 · 3.53 Impact Factor
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ABSTRACT: Protein kinase A (PKA) and other signaling molecules are spatially restricted within neurons by A-kinase anchoring proteins (AKAPs). Although studies on compartmentalized PKA signaling have focused on postsynaptic mechanisms, presynaptically anchored PKA may contribute to synaptic plasticity and memory because PKA also regulates presynaptic transmitter release. Here, we examine this issue using genetic and pharmacological application of Ht31, a PKA anchoring disrupting peptide. At the hippocampal Schaffer collateral CA3-CA1 synapse, Ht31 treatment elicits a rapid decay of synaptic responses to repetitive stimuli, indicating a fast depletion of the readily releasable pool of synaptic vesicles. The interaction between PKA and proteins involved in producing this pool of synaptic vesicles is supported by biochemical assays showing that synaptic vesicle protein 2 (SV2), Rim1, and SNAP25 are components of a complex that interacts with cAMP. Moreover, acute treatment with Ht31 reduces the levels of SV2. Finally, experiments with transgenic mouse lines, which express Ht31 in excitatory neurons at the Schaffer collateral CA3-CA1 synapse, highlight a requirement for presynaptically anchored PKA in pathway-specific synaptic tagging and long-term contextual fear memory. These results suggest that a presynaptically compartmentalized PKA is critical for synaptic plasticity and memory by regulating the readily releasable pool of synaptic vesicles.Neurobiology of Learning and Memory 05/2014; DOI:10.1016/j.nlm.2014.05.005 · 4.04 Impact Factor