Lithium Restores Neurogenesis in the Subventricular Zone of the Ts65Dn Mouse, a Model for Down Syndrome

Dipartimento di Fisiologia Umana e Generale, Università di Bologna, Bologna, Italy.
Brain Pathology (Impact Factor: 3.84). 04/2009; 20(1):106-18. DOI: 10.1111/j.1750-3639.2008.00246.x
Source: PubMed


Down syndrome (DS), a high-incidence genetic pathology, involves brain hypoplasia and mental retardation. Emerging evidence suggests that reduced neurogenesis may be a major determinant of brain underdevelopment in DS. To establish whether it is possible to improve neurogenesis in DS, Ts65Dn mice--the most widely used model for DS--and euploid mice were treated with control or lithium chow for 1 month. During the last 3 days animals received one daily injection of 5-bromo-2-deoxyuridine (BrdU)--a marker of proliferating cells--and were sacrificed 24 h after the last injection. Neurogenesis was examined in the subventricular zone (SVZ), a region that retains a neurogenic potential across life. We found that Ts65Dn mice had less (-40%) BrdU+ cells than euploid mice, indicating severe proliferation impairment. Treatment with lithium increased the number of Brdu+ cells in both euploid and Ts65Dn mice. In the latter the number of Brdu+ cells became similar to that of untreated euploid mice. Our study shows that lithium is able to restore cell proliferation in the SVZ of the Ts65Dn mouse and point at treatments with mood stabilizers as a potential tool to improve neurogenesis in patients with DS.

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    • "Widespread neurogenesis impairment has been documented in fetuses with DS (Contestabile et al., 2007; Guidi et al., 2008, 2011) and in mouse models of DS (Chakrabarti et al., 2007; Bianchi et al., 2010a,b; Trazzi et al., 2011) during critical brain developmental stages and is one of the major determinants of ID in DS. Proliferation impairment is worsened by a reduction in the acquisition of a neuronal phenotype and a relative increase in astrogliogenesis. "
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    ABSTRACT: Intellectual disability (ID) is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Accumulating evidence shows that DS is characterized by numerous neurodevelopmental alterations among which the reduction of neurogenesis, dendritic hypotrophy and connectivity alterations appear to play a particularly prominent role. Although the mechanisms whereby gene triplication impairs brain development in DS have not been fully clarified, it is theoretically possible to correct trisomy-dependent defects with targeted pharmacotherapies. This review summarizes what we know about the effects of pharmacotherapies during different life stages in mouse models of DS. Since brain alterations in DS start to be present prenatally, the prenatal period represents an optimum window of opportunity for therapeutic interventions. Importantly, recent studies clearly show that treatment during the prenatal period can rescue overall brain development and behavior and that this effect outlasts treatment cessation. Although late therapies are unlikely to exert drastic changes in the brain, they may have an impact on the hippocampus, a brain region where neurogenesis continues throughout life. Indeed, treatment at adult life stages improves or even rescues hippocampal neurogenesis and connectivity and hippocampal-dependent learning and memory, although the duration of these effects still remains, in the majority of cases, a matter of investigation. The exciting discovery that trisomy-linked brain abnormalities can be prevented with early interventions gives us reason to believe that treatments during pregnancy may rescue brain development in fetuses with DS. For this reason we deem it extremely important to expedite the discovery of additional therapies practicable in humans in order to identify the best treatment/s in terms of efficacy and paucity of side effects. Prompt achievement of this goal is the big challenge for the scientific community of researchers interested in DS.
    Frontiers in Behavioral Neuroscience 10/2015; 9. DOI:10.3389/fnbeh.2015.00265 · 3.27 Impact Factor
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    • "Ts65Dn mice also display increased astrogliogenesis [7] [27] [28] and reduced neurogenesis [8] [12], motivating interest in uncovering novel therapeutic strategies to target hippocampal neurogenesis as a means to improve cognitive function in individuals with DS. Some of the neurogenic and cognitive deficits in Ts65Dn mice can be reversed with pharmacological intervention [2] [6] [13] [14] [19] [33] [37] or environment enrichment strategies [9] [26]. These studies underscore the potential of harnessing neurogenesis to improve cognition in individuals with DS. "
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    ABSTRACT: Down Syndrome (DS) is the most common genetic cause of intellectual disability and developmental delay. In addition to cognitive dysfunction, DS patients are marked by diminished neurogenesis, a neuropathological feature also found in the Ts65Dn mouse model of DS. Interestingly, manipulations that enhance neurogenesis-like environmental enrichment or pharmacological agents-improve cognition in Ts65Dn mice. P7C3 is a proneurogenic compound that enhances hippocampal neurogenesis, cell survival, and promotes cognition in aged animals. However, this compound has not been tested in the Ts65Dn mouse model of DS. We hypothesized that P7C3 treatment would reverse or ameliorate the neurogenic deficits in Ts65Dn mice. To test this, adult Ts65Dn and age-matched wild-type (WT) mice were administered vehicle or P7C3 twice daily for 3 months. After 3 months, brains were examined for indices of neurogenesis, including quantification of Ki67, DCX, activated caspase-3 (AC3), and surviving BrdU-immunoreactive(+) cells in the granule cell layer (GCL) of the hippocampal dentate gyrus. P7C3 had no effect on total Ki67+, DCX+, AC3+, or surviving BrdU+ cells in WT mice relative to vehicle. GCL volume was also not changed. In keeping with our hypothesis, however, P7C3-treated Ts65Dn mice had a significant increase in total Ki67+, DCX+, and surviving BrdU+ cells relative to vehicle. P7C3 treatment also decreased AC3+ cell number but had no effect on total GCL volume in Ts65Dn mice. Our findings show 3 months of P7C3 is sufficient to restore the neurogenic deficits observed in the Ts65Dn mouse model of DS. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Neuroscience Letters 02/2015; 591. DOI:10.1016/j.neulet.2015.02.008 · 2.03 Impact Factor
    • "Neurogenesis during development is also impaired in DS and fewer neurons are found in the cortex, hippocampus, and other regions of DS fetuses and children (Wisniewski 1990 ; Guidi et al. 2008 ; Larsen et al. 2008 ), and there are fewer dividing cells in the DG and neocortical germinal matrix of DS fetuses (Contestabile et al. 2007 ). These and other defi cits in neurogenesis, including defective adult neurogenesis , are also observed in DS models such as Ts65Dn and Ts1Cje mice, and they appear to be due to cell cycle alterations (Clark et al. 2006 ; Chakrabarti et al. 2007 ; Contestabile et al. 2007 ; Bianchi et al. 2009 ; Ishihara et al. 2009 ). Impaired proliferation of cerebellar precursors and increased cell death have also been reported in Ts65Dn mice (Contestabile et al. 2009 ), and this may account for the reduced cerebellar size of DS-affected individuals. "
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    ABSTRACT: DSCAMs (Down syndrome cell adhesion molecules) are a group of immunoglobulin-like transmembrane proteins that contain fibronectin III domains. The founding member of the family was isolated in a positional cloning study that sought to identify genes located on chromosome 21 at the locus 21q22.2-q22.3 that is implicated in the neurological and cardiac phenotypes associated with Down's syndrome. In Drosophila, Dscam proteins are involved in neuronal wiring, while in vertebrates, the role of these cell adhesion molecules in neurogenesis, dendritogenesis, axonal outgrowth, synaptogenesis, and synaptic plasticity is only just beginning to be understood. In this chapter, we will review the functions ascribed to the two paralogous proteins found in humans, DSCAM and DSCAML1 (DSCAM-like 1), based on findings in knockout mice. The signaling pathways downstream of DSCAM activation and the role of DSCAM miss-expression in disease will be also discussed, particularly with regard to the intellectual disability in Down's syndrome.
    Cell Adhesion Molecules: Implications in Neurological Diseases, Edited by Vladimir Berezin and Peter S. Walmod, 10/2014: chapter 11: pages 249-270; Springer., ISBN: 978-1-4614-8089-1
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