title: 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.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy. andrea.contestabile@iit.it
authors.forename: Andrea
authors.initials: A
authors.lastname: Contestabile
authors.forename: Barbara
authors.initials: B
authors.lastname: Greco
authors.forename: Diego
authors.initials: D
authors.lastname: Ghezzi
authors.forename: Valter
authors.initials: V
authors.lastname: Tucci
authors.forename: Fabio
authors.initials: F
authors.lastname: Benfenati
authors.forename: Laura
authors.initials: L
authors.lastname: Gasparini
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004314:Down Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007858:Learning / Q000187:drug effects; D008094:Lithium / Q000494:pharmacology; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008817:Mice, Mutant Strains; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
chemical_list: D000928:Antidepressive Agents; D016651:Lithium Carbonate; D008094:Lithium