Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down Syndrome: Activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer

Abstract

Down Syndrome (DS) is the most prevalent form of mental retardation caused by genetic abnormalities in humans. This has been successfully modeled in mice to generate the Ts65Dn mouse, a genetic model of DS. This transgenic mouse model shares a number of physical and functional abnormalities with people with DS, including changes in the structure and function of neuronal circuits. Significant abnormalities in noradrenergic (NE-ergic) afferents from the locus coeruleus to the hippocampus, as well as deficits in NE-ergic neurotransmission are detected in these animals. In the current study we characterized in detail the behavioral phenotype of Ts65Dn mice, in addition to using pharmacological tools for identification of target receptors mediating the learning and memory deficits observed in this model of DS. We undertook a comprehensive approach to mouse phenotyping using a battery of standard and novel tests encompassing: i) locomotion (Activity Chamber, PhenoTyper, and CatWalk), ii) learning and memory (spontaneous alternation, delayed matching-to-place water maze, fear conditioning, and Intellicage), and iii) social behavior. Ts65Dn mice showed increased locomotor activity in novel and home cage environments. There were significant and reproducible deficits in learning and memory tests including spontaneous alternation, delayed matching-to-place water maze, Intellicage place avoidance and contextual fear conditioning. Although Ts65Dn mice showed no deficit in sociability in the 3-chamber test, a marked impairment in social memory was detected. Xamoterol, a β1-adrenergic receptor (β1-ADR) agonist, effectively restored the memory deficit in contextual fear conditioning, spontaneous alternation and novel object recognition. These behavioral improvements were reversed by betaxolol, a selective β1-ADR antagonist. In conclusion, our results demonstrate that this mouse model of Down Syndrome display cognitive deficits which is mediated by imbalance in noradrenergic system. In this experimental model of Down Syndrome a selective activation of β1-ADR does restore some of these behavioral deficits. Further mechanistic studies will be needed to investigate the failure of noradrenergic system and the role of β1-ADR in cognitive deficit and pathogenesis of DS in people. Restoring NE neurotransmission or a selective activation of β1-ADR need to be further investigated for development of any potential therapeutic strategies for symptomatic relieve of memory deficit in DS. Furthermore, due to the significant involvement of noradrenergic system in the cardiovascular function further safety and translational studies will be needed to ensure the safety and efficacy of this approach.

Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome

“…Consistent with other studies, we have previously detected no impairment in the amygdala-based cued-learning in Ts65Dn mice (14,27,28); therefore, we limited our fear conditioning test to contextual learning in this study (Methods in Supplement 1). To minimize the effects of circadian rhythm alterations (29), all mice were analyzed at the same time of the day.…”

“…Furthermore, we found a significant (F 1,88 ¼ 6.39, **p ¼ .013) increase in freezing in Ts65Dn mice treated with formoterol, compared with those treated with nadolol (2N-formoterol, n ¼ 7; 2N-nadolol, n ¼ 15; Ts65Dn-nadolol, n ¼ 11; Ts65Dn-formoterol, n ¼ 7). (14,27). However, because 50% of people with DS exhibit cardiovascular abnormalities (42), the use of β2AR agonists might be safer in people with DS, because they might induce less peripheral cardiovascular side effects as compared with β1ARs.…”

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

“…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).…”

Improving Memory and Cognition in Individuals with Down Syndrome

“…A significant improvement in contextual fear conditioning was found after treatment of Ts65Dn mice with droxidopa (l-threo-3,4-dihydroxyphenylserine; L-DOPS), a norepinephrine precursor [18]. In addition, treatment with the b1-adrenergic receptor agonist xamoterol rescued some of the learning deficits in Ts65Dn mice [19]. These results suggest that behavioral deficits observed in the Ts65Dn mouse may be mediated by an imbalance in the noradrenergic system and be potentially reversible.…”