Aim: 

Mental retardation in Down syndrome (DS), a high incidence genetic disease, has been attributed to reduced neurogenesis during brain development. The aim of our study was to establish whether it is possible to improve neurogenesis in DS by pharmacological treatment with lithium, a widely used antidepressant.

Methods: 

Adult Ts65Dn mice, the most widely used animal model for DS and euploid mice were treated with control or lithium chow for one month. During the last three days of treatment animals received one daily injection of BrdU, a marker of proliferating cells and were sacrificed 24 hr after the last injection. Brains were removed, cut in 30 mm-thick sections and processed for single or double immunofluorescence histochemistry. Neurogenesis was examined in the subventricular zone (SVZ), a region that is the source of cortical neurons during embryogenesis and retains a neurogenic potential across life.

Results: 

We found that Ts65Dn mice had less (-40%) BrdU+ cells than euploid mice, indicating severe proliferation impairment, and less Ki-67+ cells, indicating a reduction in the pool of precursors. Looking at the phenotype of the proliferating cells we found proliferation impairment of all types of precursors (neuroblasts, astrocytes, transient amplifying cells) present in the SVZ. Treatment with lithium increased the number of Brdu+ and Ki-67+ cells in both euploid and Ts65Dn mice. In the latter the number of Brdu+ and Ki-67+ cells after lithium treatment became similar to that of untreated euploid mice. Importantly, the proliferation improvement involved all types of precursors.

Conclusions: 

Our study shows that lithium is able to completely restore cell proliferation in the SVZ of the Ts65Dn mouse and point at treatments with antidepressants as a potential tool to improve neurogenesis in patients with DS.