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Lithium rescues synaptic plasticity and memory in Down syndrome mice
Andrea Contestabile, … , Fabio Benfenati, Laura Gasparini
Andrea Contestabile, … , Fabio Benfenati, Laura Gasparini
Published December 3, 2012
Citation Information: J Clin Invest. 2013;123(1):348-361. https://doi.org/10.1172/JCI64650.
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Research Article Neuroscience Article has an altmetric score of 33

Lithium rescues synaptic plasticity and memory in Down syndrome mice

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Abstract

Down syndrome (DS) patients exhibit abnormalities of hippocampal-dependent explicit memory, a feature that is replicated in relevant mouse models of the disease. Adult hippocampal neurogenesis, which is impaired in DS and other neuropsychiatric diseases, plays a key role in hippocampal circuit plasticity and has been implicated in learning and memory. However, it remains unknown whether increasing adult neurogenesis improves hippocampal plasticity and behavioral performance in the multifactorial context of DS. We report that, in the Ts65Dn mouse model of DS, chronic administration of lithium, a clinically used mood stabilizer, promoted the proliferation of neuronal precursor cells through the pharmacological activation of the Wnt/β-catenin pathway and restored adult neurogenesis in the hippocampal dentate gyrus (DG) to physiological levels. The restoration of adult neurogenesis completely rescued the synaptic plasticity of newborn neurons in the DG and led to the full recovery of behavioral performance in fear conditioning, object location, and novel object recognition tests. These findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult DS mice rescues hippocampal plasticity and memory and implicate adult neurogenesis as a promising therapeutic target to alleviate cognitive deficits in DS patients.

Authors

Andrea Contestabile, Barbara Greco, Diego Ghezzi, Valter Tucci, Fabio Benfenati, Laura Gasparini

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Figure 7

Lithium rescued proliferation of Ts65Dn NPCs through stimulation of β-catenin pathway.

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Lithium rescued proliferation of Ts65Dn NPCs through stimulation of β-ca...
(A) Multiplex fluorescence Western blot analysis of active form of β-catenin in hippocampal lysates from WT and Ts65Dn mice. The ratio of active β-catenin (green) to total β-catenin (red). 2-way ANOVA: genotype (F1,12 = 8.576, P = 0.013), treatment (F1,12 = 41.168, P < 0.001), genotype × treatment (F1,12 = 8.439, P = 0.013). (B) ADNPC immunoreactivity for the progenitor markers Sox2 (green) and Nestin (red). (C) BrdU immunoreactivity (green) in ADNPCs counterstained with DAPI (red). Scale bars: 20 μm. (D) Percentage of BrdU+ cells in Ts65Dn ADNPCs treated with lithium (2 mM LiCl ) or vehicle. 2-way ANOVA: genotype (F1,12 = 17.431, P < 0.001), treatment (F1,12 = 19.044, P < 0.001), genotype × treatment (F1,12 = 0.317, P = 0.584), (n = 4). (E) Wnt/β-catenin pathway activation as detected using the TOPFlash and FOPFlash plasmid luciferase reporter assay. Treatment with lithium increased luciferase activity in ADNPCs under basal conditions (1-way ANOVA [F3,20 = 7.448, P = 0.002]) and upon stimulation with 10 ng/ml of Wnt3a (1-way ANOVA [F3,20 = 14.643, P < 0.001]). (F) Proliferation analysis in ADNPCs transfected with dnTCF-mCherry (EdTC) or control mCherry plasmids. Proliferation was expressed as the ratio of BrdU+mCherry+ double-labeled cells to total mCherry+ cells (n = 4). 2-way ANOVA: genotype (F1,24 = 357.0, P < 0.001), treatment (F3,24 = 194.0, P < 0.001), genotype × treatment (F3,24 = 8.446, P < 0.001). *P < 0.05; **P < 0.01, Tukey’s post hoc test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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