Fiorentini

Lithium Improves Hippocampal Neurogenesis, Neuropathology and Cognitive Functions in APP Mutant Mice
Anna Fiorentini, Maria Cristina Rosi, Cristina Grossi, Ilaria Luccarini, Fiorella Casamenti*
Department of Pharmacology, University of Florence, Florence, Italy

Abstract
Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive deterioration ofcognitive functions, extracellular b-amyloid (Ab) plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. Methodology/Principal Findings: The double transgenic (Tg) CRND8 mice (overexpressing the Swedishand Indiana mutations in the human amyloid precursor protein), aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. Thedifferentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3b and subsequent activation ofWnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium’s ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines as brain Ab deposition and pathology increases. Conclusions: Lithium, when given on time, stimulates neurogenesis andcounteracts AD-like pathology.
Citation: Fiorentini A, Rosi MC, Grossi C, Luccarini I, Casamenti F (2010) Lithium Improves Hippocampal Neurogenesis, Neuropathology and Cognitive Functions in APP Mutant Mice. PLoS ONE 5(12): e14382. doi:10.1371/journal.pone.0014382 Editor: Troy Zars, University of Missouri, United States of America Received July 14, 2010; Accepted November 19, 2010; PublishedDecember 20, 2010 Copyright: ß 2010 Fiorentini et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from Ministero dell’Istruzione, dell’Universita’ e della Ricerca(PRIN2008R25HBW_01) and Universita’ degli Studi di Firenze, Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: fiorella.casamenti@unifi.it

Introduction
In the adult Central Nervous System (CNS), neurogenesis occurs throughout thelifetime. Adult neurogenesis is a process by which new neurons are produced from neural stem cells (NSCs) and has consistently been found in two ‘‘neurogenic regions’’ of the brain in vivo: the subgranular zone (SGZ) of dentate gyrus (DG) in the hippocampus, which supplies new neurons for the dentate granular cell layer (GCL) and the subventricular zone (SVZ) lining the lateral ventricles in theforebrain, which supplies new interneurons for the olfactory bulb [1],[2]. Adult NSCs have the ability to self-renew and to differentiate into neurons, astrocytes and oligodendrocytes in all mammalian CNS, including humans [3]. In both SGZ and SVZ neurogenic regions, neurogenesis progress as a multi-step process which starts with the proliferation of NSCs. For the hippocampus, conceptually, this...