Deficiency of Adult Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome

Abstract

Neurogenesis in the mammalian adult brain is a well established phenomenon (for the recent reviews see Carpentier & Palmer, 2009; Kaneko & Sawamoto, 2009; Rodriguez & Verkhratsky, 2011) that is important in both young and aging brain (Galvan & Jin, 2007; Rao et al., 2006). The subventricular zone, subgranular layer of the dentate gyrus (DG), and cortex are the main sites of adult neurogenesis (Gould et al., 1999; Luskin & Boone, 1994; Palmer et al., 2000; Seki et al., 2007; Yoneyama et al., 2011). Newly-born neurons during adult neurogenesis have the ability to integrate into previously established neuronal networks (Kee et al., 2007; Markakis & Gage, 1999; Sandoval et al., 2011). Alteration of neurogenesis under different experimental and pathological conditions has been described to a great extent (Rodriguez & Verkhratsky, 2011; Sandoval et al., 2011; Winner et al., 2011; Yoneyama et al., 2011; Yu et al., 2009). Significant decreases of neurogenesis have been found in neurodevelopmental (Contestabile et al., 2007; Guidi et al., 2008, 2010) and in neurodegenerative diseases (Rodriguez & Verkhratsky, 2011). Numerous studies provide evidence that a lack of neurogenesis significantly diminishes plasticity in the adult brain and interferes with learning and memory (reviewed in Koehl & Abrous, 2011; Mongiat & Schinder, 2011). Different mechanisms have been proposed to regulate neurogenesis in the adult brain, including brain injury (Kernie & Parent, 2010; Moriyama et al., 2011), ischemia (Kernie & Parent, 2010; Kreuzberg et al., 2010), and inflammation (Voloboueva et al., 2010). One of the least studied factors that affects neurogenesis are chromosomal aberrations. Down syndrome (DS) results from the extra copy of chromosome 21 occurring with a prevalence of 1 in 733 live births (Canfield et al., 2006). Subjects with DS show developmental regression, diminished cognitive ability, and autonomic dysfunction (Antonarakis & Epstein, 2006; Chapman & Hesketh, 2000). The DS brain is severely affected showing a reduction in both overall size and of particular areas (frontal cortex, hippocampus, cerebellum, and brainstem) due to a reduced number of neurons (Aylward et al., 1997, 1999; Kesslak et al., 1994; Pinter et al., 2001; Raz et al., 1995; Wisniewski et al., 1984).