Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome

Abstract

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 norepinephrine 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 beta(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.

Xamoterol impairs hippocampus-dependent emotional memory retrieval via Gi/o-coupled β2-adrenergic signaling

“…F (1,18) ¼ 6.5 and P ¼ 0.021 for the main effect of pretreatment; F (1,18) ¼ 10.1 and P ¼ 0.006 for the main effect of treatment; and F (1,18) ¼ 9.9 and P ¼ 0.006 for the inter- Relevant to this, the locus coeruleus has been found to degenerate in Down syndrome (Mann et al 1985;Marcyniuk et al 1988). In a mouse model of Down syndrome (Ts65Dn), there is less CNS NE, fewer locus coeruleus adrenergic neurons, and more b receptorpositive neurons in the hippocampus, suggesting the presence of functional NE deficiency (Dierssen et al 1997;Salehi et al 2009). Similar to Dbh 2/2 mice, Ts65Dn mice display deficits in contextual fear memory retrieval but not in cued fear memory, and administration of a NE precursor or xamoterol reverses the impairment of memory retrieval in Ts65Dn mice by activating central b 1 receptors (Salehi et al 2009;Faizi et al 2011).…”

“…In a mouse model of Down syndrome (Ts65Dn), there is less CNS NE, fewer locus coeruleus adrenergic neurons, and more b receptorpositive neurons in the hippocampus, suggesting the presence of functional NE deficiency (Dierssen et al 1997;Salehi et al 2009). Similar to Dbh 2/2 mice, Ts65Dn mice display deficits in contextual fear memory retrieval but not in cued fear memory, and administration of a NE precursor or xamoterol reverses the impairment of memory retrieval in Ts65Dn mice by activating central b 1 receptors (Salehi et al 2009;Faizi et al 2011).…”

FoxO6 regulates memory consolidation and synaptic function

“…The trace tone-cued fear-conditioning experiment with FoxO6 mutant and wild-type siblings used two different contexts, A and B, and was performed according to Saxe et al (2006) with the modification described in Salehi et al (2009) using a fear-conditioning chamber from Coulbourn Instruments. On the first day, mice were individually placed in context A and, after 3 min, received five tone-shock pairing cycles (tone is referred to as a conditional stimulus [CS], and the shock is referred to as an unconditional stimulus [US]).…”

“…We first used contextual fear conditioning, a robust associative learning task that requires a functional hippocampus and amygdala (Kim and Fanselow 1992;Chowdhury et al 2005;Salehi et al 2009). In this test, a mild electric foot shock (unconditional stimulus) is paired to a specific context and a tone cue trace (conditional stimulus) ( Fig.…”

From Molecules to Behavior: Lessons from the Study of Rare Genetic Disorders

“…A special diet to prevent the metabolic disorder from birth reduces the cognitive and behavioural symptoms and, inter alia, improves the actual cognitive processes (Carlier and Ayoun 2007;Williams et al 2008). Of course it is also true that several successful treatment strategies identified in mouse models of rare genetic diseases have led to clinical trials (Salehi et al 2009;Roux et al 2007;Varela et al 2008). It is striking how many rare diseases have become powerful models of translational medicine and translational neuroscience, exactly because these diseases have allowed us to progress from an understanding of their underlying mechanisms to the brain and behavioural phenotypes.…”