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

Lithium rescues synaptic plasticity and memory in Down syndrome mice

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 2

Restoration of adult neurogenesis rescued newborn neuron–dependent synaptic plasticity in the DG of Ts65Dn mice.

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Restoration of adult neurogenesis rescued newborn neuron–dependent synap...
fEPSPs in the DG medial molecular layer elicited through the stimulation of the MPP in ACSF were recorded in hippocampal slices obtained from Ts65Dn and WT mice fed with normal or lithium-containing diets for either 1 or 4 weeks. (A) Position of the stimulating and recording electrodes. (B) ACSF-LTP was induced in hippocampal slices from saline-treated WT (P < 0.01 vs. baseline) but not Ts65Dn mice (P = 0.190). (C) ACSF-LTP was restored in hippocampal slices of Ts65Dn mice (P < 0.01) and increased in slices from WT littermates (P < 0.01) after 4 weeks of lithium treatment. (D) ACSF-LTP was inhibited through the specific NR2B antagonist Ro25-6981 (1.5 μM) in hippocampal slices from WT (P = 0.469) and Ts65Dn (P = 0.091) mice treated with lithium for 4 weeks. (E) ACSF-LTP was induced in hippocampal slices of WT (P < 0.001) but not Ts65Dn (P = 0.802) mice treated with lithium for only 1 week. The insets in B–E show representative fEPSP traces recorded 5 minutes before (black) and 45 minutes after (gray) LTP induction. (F) Quantification of ACSF-LTP elicited in the DG of WT and Ts65Dn mice. Numbers in parentheses indicate the number of slices recorded for each experimental group. 2-way ANOVA: genotype (F1,43 = 16.721, P < 0.001), treatment (F3,43 = 25.431, P < 0.001), genotype × treatment (F3,43 = 4.996, P = 0.005). *P < 0.05; **P < 0.01, Tukey’s post hoc test.