Aging rather than aneuploidy affects monoamine neurotransmitters in brain regions of Down syndrome mouse models

Abstract

Altered concentrations of monoamine neurotransmitters and metabolites have been repeatedly found in people with Down syndrome (DS, trisomy 21). Because of the limited availability of human post-mortem tissue, DS mouse models are of great interest to study these changes and the underlying neurobiological mechanisms. Although previous studies have shown the potential of Ts65Dn mice – the most widely used mouse model of DS – to model noradrenergic changes, a comprehensive monoaminergic characterization in multiple brain regions has not been performed so far. Here, we used RP-HPLC with electrochemical detection to quantify (nor)adrenergic (NA, adrenaline and MHPG), dopaminergic (DA, HVA and DOPAC), and serotonergic compounds (tryptophan, 5-HT and 5-HIAA) in ten regionally dissected brain regions of Ts65Dn mice, as well as in Dp1Tyb mice – a novel DS mouse model. Comparing young adult aneuploid mice (2.5–5.5 months) with their euploid WT littermates did not reveal generalized monoaminergic dysregulation, indicating that the genetic overload in these mice barely affected the absolute concentrations at this age. Moreover, we studied the effect of aging in Ts65Dn mice: comparing aged animals (12–13 months) with their younger counterparts revealed a large number of significant changes. In general, the (nor)adrenergic system appeared to be reduced, while serotonergic compounds were increased with aging. Dopaminergic alterations were less consistent. These overall patterns appeared to be relatively similar for Ts65Dn and WT mice, though more observed changes were regarded significant for WT mice. Similar human post-mortem studies are necessary to validate the monoaminergic construct validity of the Ts65Dn and Dp1Typ mouse models.

Rapamycin Treatment Ameliorates Age-Related Accumulation of Toxic Metabolic Intermediates in Brains of the Ts65Dn Mouse Model of Down Syndrome and Aging

“…A recent study employed an electrochemical (amperometric) detection method coupled with HPLC to analyze monoamine metabolites in the dopaminergic, serotonergic, and (nor)adrenergic neurotransmission systems in brains from a mouse model of DS ( Dekker et al, 2017 ). They report changes mainly associated with aging, rather than aneuploidy, consistent with the changes we observed in our analysis.…”

Outer Brain Oscillations in Down Syndrome

“…The pending questions are whether these alterations in oscillatory activity are related to changes in the effective functional inhibition, and also which is the alteration in the cortical circuitry that is supporting impairment in oscillatory activity. A monoaminergic unbalance –i.e., noradrenaline and serotonine- has been also described in aging DS humans (Dekker et al, 2017), which may be reated to the observed slowing of the EEG oscillatory activity. In turn, there are consistent evidences that the GABAergic system is responsible of generating gamma oscillations (Cardin et al, 2009; Buzsáki and Wang, 2012; Siegel et al, 2012).…”

Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome

“…It has also been reported that there is reduced expression of DA receptors D1R and D2R in the brains of patients with DS [10]. As observed in patients with DS, varied amounts of DA have also been reported in mouse models of DS [6, 7, 11, 12], suggesting that variable DA levels are associated with abnormal brain development. However, the role of the DA signaling system in DS pathology has yet to be analyzed at a cellular level.…”