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 1

Lithium restored the number of newborn neurons in DG of adult Ts65Dn mice.

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Lithium restored the number of newborn neurons in DG of adult Ts65Dn mic...
(A) Expression of molecular markers during adult DG neurogenesis. During the mitotic phase, 2 types of progenitors proliferate in the SGZ of the DG: RGL progenitors (type I cells, expressing Nestin, GFAP, and Sox2) and amplifying progenitors (type II cells, expressing Sox2 only). Before becoming postmitotic, the progenitors undergo a short intermediate stage (neuroblasts), commit to the neuronal fate, and begin expressing DCX. In the postmitotic phase, DCX-positive newborn neurons derived from neuroblasts undergo a morphological and physiological maturing process with the sequential expression of CR and NeuN upon final maturation. (B–E) Five- to six-month-old Ts65Dn and WT mice were treated with lithium or saline for 4 weeks, and the number of newborn neurons was evaluated through immunohistochemistry for DCX or CR (red) and counterstained with Hoechst-33342 (blue). (B) Immunoreactivity and (C) number of DCX+ newborn neurons in saline- or lithium-treated Ts65Dn and WT mice. 2-way ANOVA: genotype (F1,20 = 19.285, P < 0.001), treatment (F1,20 = 25.570, P < 0.001), genotype × treatment (F1,20 = 0.584, P = 0.454). (D) Immunoreactivity and (E) number of CR+ newborn neurons in DG of saline- or lithium-treated Ts65Dn and WT mice. 2-way ANOVA: genotype (F1,20 = 2.413, P = 0.136), treatment (F1,20 = 26.602, P < 0.001), genotype × treatment (F1,20 = 2.247, P = 0.149). Numbers in parentheses indicate the number of animals in each group. *P < 0.05; **P < 0.01, Tukey’s post hoc test. Scale bars: 100 μm (B); 25 μm (D).