Down syndrome (DS), a neurodevelopmental disorder caused by trisomy of chromosome 21, is the leading cause of inherited intellectual disability. The brains of patients with DS exhibit suboptimal neural network architecture, altered synaptic communication, and impaired neurogenesis, resulting in cognitive deficits. Contestabile et al. assessed the effects of lithium, a clinically utilized drug, on the restoration of neurogenesis and cognitive function in a mouse model of DS. In the panels above, Contestabile and colleagues stained hippocampal sections from wild type (left) and Down syndrome (right) mice treated with saline (top panels) or lithium (bottom panels). The newborn neurons appear in light green. These results suggest that restoration of adult neurogenesis could improve cognitive function in patients with Down syndrome.
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.
Andrea Contestabile, Barbara Greco, Diego Ghezzi, Valter Tucci, Fabio Benfenati, Laura Gasparini