DOWN SYNDROME Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome A. Salehi, 1 * † M. Faizi, 2 D. Colas, 3 J. Valletta, 1‡ J. Laguna, 1 R. Takimoto-Kimura, 1 A. Kleschevnikov, 1‡ S. L. Wagner, 4 P. Aisen, 4 M. Shamloo, 2 W. C. Mobley 1‡ (Published 18 November 2009; Volume 1 Issue 7 7ra17) Down syndrome (trisomy 21) is the most common cause of mental retardation in children and leads to marked deficits in contextual learning and memory. In rodents, these tasks require the hippocampus and are mediated by several inputs, particularly those originating in the locus coeruleus. These afferents mainly use nor- epinephrine as a transmitter. To explore the basis for contextual learning defects in Down syndrome, we examined the Ts65Dn mouse model. These mice, which have three copies of a fragment of mouse chromosome 16, exhibited significant deficits in contextual learning together with dysfunction and degeneration of locus coeruleus neurons. However, the postsynaptic targets of innervation remained responsive to noradrenergic receptor agonists. Indeed, despite advanced locus coeruleus degeneration, we were able to reverse contextual learning failure by using a prodrug for norepinephrine called L-threo-3,4-dihydroxyphenylserine, or xamoterol, a b 1 -adrenergic receptor partial agonist. Moreover, an increased gene dosage of App, in the context of Down syndrome, was necessary for locus coeruleus degeneration. Our findings raise the possibility that restoring norepinephrine-mediated neurotransmission could reverse cognitive dysfunction in Down syndrome. INTRODUCTION Down syndrome (DS) is a complex genetic disorder caused by the pres- ence of a third copy of chromosome 21, resulting in triplication of ~300 genes. It is the most common source of congenital anomalies, with a prevalence of 1 per 733 live births in the United States; 5000 affected infants are born each year (1). Among several abnormalities in DS, in- tellectual deficiencies that affect the quality of life for both children and adults are of primary concern. Understanding the neurobiological basis of failed cognition in DS is thus a high priority because deciphering pathogenesis may lead to effective therapies. Failed learning and memory is essentially universal in people with DS (2). We have pursued a strategy that emphasizes the initial documen- tation of phenotypes followed by discovery of underlying gene dose effects and molecular and cellular mechanisms (3–5). Among the many deficits present in children with DS, these individuals show severe defects in con- textual tasks mediated by the hippocampus. This phenotype is both robust and significant, compromising the ability to carry out tasks of daily life. Cued recall, in which memory is elicited by certain sensory cues, is partially spared in DS (6, 7); these tasks are modulated by the amygdala and, unlike the hippocampus, this region shows no change in structure in young people with DS (8). The hippocampus is markedly affected in DS (6–8). This brain region is essential for registering events with respect to time and space (9, 10). By modulating contextual discrimination, in which spatial information is integrated with other salient features of the environment, the hippocampus is involved in generating appropriate re- sponses to dynamic changes in milieu (10). Amnesic individuals with hip- pocampal damage fail in tests of contextual learning (11). Furthermore, hippocampal and entorhinal cortex damage has been shown to produce insensitivity to contextual changes in rodents (10, 12), as has transient inactivation of the hippocampus using g-aminobutyric acid type A (GABA A ) agonists (13). Contextual discrimination is made possible by accessing information from a number of afferent systems, both sensory and modulatory; sensory information is transmitted from the entorhinal cortex, whereas modulatory inputs originate in several populations includ- ing basal forebrain cholinergic neurons (BFCNs), norepinephrine (NE)– containing neurons of the locus coeruleus (LC), serotoninergic neurons of the raphe nuclei, and calretinin-positive neurons of the supramammillary area ( 4). Modulatory inputs extensively innervate the hippocampus. With respect to contextual discrimination, the LC, which is the sole source of NE-positive inputs, appears to play a defining role through the release of NE to act on b adrenoceptors. Indeed, studies in which the activity of LC afferents or b 1 receptors was selectively inhibited showed that NE neuro- transmission is essential for this aspect of hippocampal function (14). Whether the LC plays a role in contextual discrimination in humans is yet to be determined. Essential to demonstrating a link would be studies that dissect hippocampally driven contextual learning from cued learning, in which the amygdala plays a central role. Examining disorders in which the LC degenerates is one strategy for exploring LC function in humans. LC neurons are markedly affected in Alzheimer’s disease (AD), DS, Parkinson’s disease, Huntington’s disease, dementia pugilistica, and Wernicke-Korsakov syndrome (15–21). In AD, LC neu- rons undergo more extensive degeneration than BFCNs (18) and the extensive neurofibrillary degeneration of the LC correlates well with the severity of cognitive decline (20). Furthermore, NE concentrations are significantly reduced in the temporal cortex of patients with AD (21). In DS, individuals show significant hippocampal dysfunction, including deficits in contextual discrimination (22). Although cued learning re- mains relatively intact, contextual learning is markedly impaired in both infants and adolescents with DS (7, 22); it has been suggested that such deficits significantly impair learning (6). 1 Department of Neurology and Neurological Sciences, Stanford Medical School, Stanford, CA 94305, USA. 2 Behavioral and Functional Neuroscience Laboratory, Stanford Medical School, Stanford, CA 94305, USA. 3 Department of Biology, Stanford Medical School, Stanford, CA 94305, USA. 4 Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. *To whom correspondence should be addressed. E-mail: asalehi@stanford.edu †Present address: Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA. ‡Present address: Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. RESEARCH ARTICLE www.ScienceTranslationalMedicine.org 18 November 2009 Vol 1 Issue 7 7ra17 1