Ts1Cje Down syndrome model mice exhibit environmental stimuli-triggered locomotor hyperactivity and sociability concurrent with increased flux through central dopamine and serotonin metabolism

Abstract

Down syndrome (DS) or trisomy 21 is the most common genetic cause of intellectual disability and is characterized by a myriad of phenotypes affecting various organs. Several mouse models of DS have been established and constitute useful tools for defining the etiology of DS. Ts1Cje mouse carrying a 7.6 Mb segmental trisomy of mouse chromosome 16 (MMU16) is among the most commonly used DS models. Ts1Cje mice display a subset of features that mimic human DS, notably craniofacial abnormalities and deficits in learning and memory. A number of molecular and physiological parameters are also affected in these mice, including oxidative stress increase and mitochondrial dysfunction, abnormal neuronal dendritic spines, abnormal synaptic plasticity, deficient embryonic and adult neurogenesis and enhanced cell proliferation in ganglionic eminences. Despite the occurrence of affective and emotional impairments in patients with Down syndrome, these parameters are poorly documented in Down syndrome mouse models, including Ts1Cje mice. Here, we developed a comprehensive approach using the Ts1Cje model in order to investigate eventual behavioral-molecular correlations. We designed and describe for the first time a large behavior screening focusing on spontaneous activity, social behavior, anxiety and depression-like behavior in various conditions. We coupled this study to a molecular study using both in-vivo microdialysis and tissue punch measurements of monoamines levels in brains from Ts1Cje mice. Ts1Cje mice were hyperactive and possibly less anxious compared to WT mice in novel environments, but significantly less active in familiar environments. Ts1Cje also showed increased social contacts with unfamiliar partners compared to their WT littermates in two different testing paradigms. Ts1Cje mice also exhibited signs of decreased depression like-behavior. Furthermore, Ts1Cje mice showed motor coordination deficit. As locomotor hyperactivity is often associated with enhanced striatal dopaminergic neurotransmission, we measured extracellular and total content of monoamines. By using intracerebral microdialysis and tissue extracts of the striatum and ventral forebrain, we also provide evidence that extracellular dopamine (DA) and serotonin (5-HT) and their total amounts are increased in Ts1Cje mice. In addition, we found that biosynthesis and degradation of DA was accelerated in Ts1Cje striatum by using biochemical and immunohistochemical analyses. These changes in monoamines could underlie the abnormal affective and emotional behaviors observed in Ts1Cje mice. Using a comprehensive battery of behavioral tests, we identified environmental novelty stimuli-triggered hyperactivity, increased sociability, and decreased depression-like behavior in Ts1Cje mice. Our neurochemical and immunohistochemical results further suggested that Ts1Cje mice show an abnormal increase in DA and 5-HT combined with an enhanced metabolism of these transmitters, which may help explain the affective and emotional abnormalities. Especially, reports on DA metabolism in brain samples from DS patients have been rather controversial. In some cases reported in the literature, DA was decreased in the brains of elder DS patients but not in young adult with DS. The discrepancies in human studies may be due to age-specific changes and to the fact that samples were extracted post-mortem (after natural death). Although the monoamine concentration in brains from young adults with DS is still unclear, our results suggest that it is likely not decreased. Our study suggests that more extensive investigation should thus be considered before implementing monoamine treatments in DS. Monoamine metabolism alterations still require further investigation in order to understand how they are involved in the developmental and functional deficits in the brains of DS patients. Finally, our finding contributes to the understanding of molecular pathology of DS and may inform development of effective therapeutic approaches (Shimohata et al., 2017).