Sleep–wake architecture in mouse models for Down syndrome Damien Colas, a Jacqueline London, b Abdallah Gharib, a Raymond Cespuglio, a and Nicole Sarda a, * a Unite INSERM Unit 480, Claude Bernard University, 69373 Lyon Cedex 08, France b EA 3508, Paris 7 Denis-Diderot University, 2 Place Jussieu, Case7088, 75005 Paris, France Received 13 March 2003; revised 11 February 2004; accepted 1 March 2004 Available online 21 April 2004 Sleep – wake homeostasis is crucial for behavioral performances and memory both in the general population and in patients with learning disability, among whom were Down syndrome (DS) patients. We investigated, in mouse models of DS, cortical EEG and sleep – wake architecture under baseline conditions and after a 4-h sleep deprivation (SD). Young hemizygous mice (hSODwt/+) transgenic for the human CuZn superoxide dismutase (hSOD1) or for the human amyloid precursor protein (HuAPP 695 ; hAPPwt/+) were obtained on the same FVB/N inbred background. Baseline records for slow wave sleep (SWS) and wake (W) parameters were unchanged, whereas paradoxical sleep (PS) episode numbers were decreased and PS latency increased after lights off in hSODwt/+ mice versus controls. hSODwt/+ mice did not experience SWS or PS rebounds after SD but EEG activity in the delta- SWS activity (SWA) was enhanced. hAPPwt/+ mice exhibited no change in PS but an increase in W and a decrease in SWS before light transition as well as an increase in theta-power in PS and W. After SD, hAPPwt/+ mice exhibited SWS and PS rebounds as well as enhancement of SWA. We investigated also the nitrite/nitrate levels in all mice and found an increase in the brainstem of hSODwt/+ mice only versus control ones. These preliminary data provide useful results to investigate other genetically manipulated mice and to better understand the biochemical basis of sleep disorders in DS patients. D 2004 Elsevier Inc. All rights reserved. Keywords: Down syndrome; Transgenic mice; Sleep – wake; Superoxide dismutase; Amyloid precursor protein Introduction Trisomy 21 or Down syndrome (DS) is the main autosomal aneuploidy that is not lethal in fetal or early postnatal life. DS results from the triplication of the whole or distal part of human autosome 21 (Lejeune et al., 1959) and is the primary cause of mental retardation (Caviedes et al., 1990; Epstein, 1995; Epstein et al., 1987). DS phenotypes show variable penetrance, affecting many different organs including the neural system. Among the brain abnormalities observed in DS are the smaller volumes of the cerebellum, frontal cortex and hippocampus, the enlargement of the hippocampal gyrus, the decrease cell density of the cerebellum granular layer, and the abnormal numbers and ramification of spines (Head et al., 2001; Wisniewski and Rabe, 1985). Polysomnographic recordings obtained from DS patients have shown sleep patterns abnormalities that might contribute to their poor cognitive efficien- cy and constant fatigability. These abnormalities include a reduction in the percentage of paradoxical sleep (PS), a prolonged latency before the first PS episode, an increase in undifferential sleep, and a reduced ratio of oculomotor frequencies (Andreou et al., 2002; Diomedi et al., 1999; Grubar et al., 1986; Levanon et al., 1999). Several strategies have been used for modeling DS in mice: (a) transgenic mice overexpressing single genes or a combination of genes or large fragments of DNA (human YAC and BAC) from chromosome 21 genes or their mouse homologues; (b) mouse models with segmental trisomy 16 for the App to Mx1 region (Ts65Dn) or for the Sod1 to Mx 1 region (Ts1Cje) and the new segmental trisomic (Ms1Ts65) mouse, without triplication of the region from App to Sod1 (for reviews, see Dierssen et al., 2001; Galdzicki and Siarey, 2003; Sago et al., 2000). Human Cu/Zn superoxide dismutase 1 gene (hSOD1), the first chromosome 21 gene to be fully characterized (Groner et al., 1985) was shown to be overexpressed at the protein level in DS patients (Sinet et al., 1975). Transgenic mice expressing wild-type hSOD1 (hSOD1wt) were the first animal model for DS (Epstein et al., 1987). SOD1 overexpression was shown to be protective against in vivo insults as glutamate and MPTP toxicity (Chan et al., 1990; Przedborski et al., 1992) but deleterious for aging processes (Kola and Herzog, 1998). Transgenic SOD1 mice exhibit some abnormalities present in DS patients: neuromuscular abnormalities of the tongue and the legs (Avraham et al., 1991), cognitive deficit and impairment in long-term potentiation (LTP) (Gahtan et al., 1998), premature thymic involution (Nabarra et al., 1996), and diminished serotonin uptake in platelets (Schickler et al., 1989). The amyloid precursor protein (APP) gene is localized on chromosome 21, and APP abnormal metabolism is the primary 0969-9961/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2004.03.009 Abbreviations: AD, Alzheimer’s disease; APP, Amyloid precursor protein; Ah, amyloid-h peptide; CNS, central nervous system; DS, Down’s syndrome; EEG, electroencephalogram; hSOD1, human CuZn superoxide dismutase 1; iNOS, inducible nitric oxide synthase; PS, paradoxical sleep; SWS, slow wave sleep; SWA, slow wave activity; W, wakefulness. * Corresponding author. Neurobiologie des Etats de Sommeil et d’Eveil, Faculte ´ de Me ´decine Rockefeller, Universite ´ Claude Bernard, Unite ´ INSERM U. 480, 8 avenue Rockefeller, 69373 Lyon Cedex 08, France. Fax: +33-4-78-77-71-72. E-mail address: sarda@laennec.univ-lyon1.fr (N. Sarda). Available online on ScienceDirect (www.sciencedirect.com.) www.elsevier.com/locate/ynbdi Neurobiology of Disease 16 (2004) 291 – 299