Reduced cortical neurotransmitter receptor complex levels in fetal Down syndrome brain

Falsafi, Soheil Keihan; Dierssen, Mara; Ghafari, Maryam; Pollak, Arnold; Lubec, Gert

doi:10.1007/s00726-015-2062-6

Cited by 11 publications

(5 citation statements)

References 68 publications

(66 reference statements)

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“…In young Ts65Dn mice, we found reduced DA levels in the (hypo)thalamus. In the human situation, levels of DA and the DA receptor 1-containing complex were significantly lower in the frontal cortex of DS fetuses than in age-matched control fetuses ( Keihan Falsafi et al, 2016 , Whittle et al, 2007 ). Furthermore, the lack of significant alterations between the older Ts65Dn and WT Ts65Dn mice resembles the lack of significant changes in multiple post-mortem brain samples of DS individuals vs. controls ( Godridge et al, 1987 ).…”

Section: Discussionmentioning

confidence: 83%

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

Dekker

Vermeiren

Albac

et al. 2017

Neurobiology of Disease

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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.

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Section: Discussionmentioning

confidence: 83%

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

Dekker

Vermeiren

Albac

et al. 2017

Neurobiology of Disease

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“…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.…”

Section: Introductionmentioning

confidence: 93%

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

et al. 2018

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BackgroundDown syndrome (DS) is a common developmental disorder resulting from the presence of an additional copy of chromosome 21. Abnormalities in dopamine signaling are suggested to be involved in cognitive dysfunction, one of the symptoms of DS, but the pathophysiological mechanism has not been fully elucidated at the cellular level. Stem cells from human exfoliated deciduous teeth (SHED) can be prepared from the dental pulp of primary teeth. Importantly, SHED can be collected noninvasively, have multipotency, and differentiate into dopaminergic neurons (DN). Therefore, we examined dopamine signaling in DS at the cellular level by isolating SHED from a patient with DS, differentiating the cells into DN, and examining development and function of DN.MethodsHere, SHED were prepared from a normal participant (Ctrl-SHED) and a patient with DS (DS-SHED). Initial experiments were performed to confirm the morphological, chromosomal, and stem cell characteristics of both SHED populations. Next, Ctrl-SHED and DS-SHED were differentiated into DN and morphological analysis of DN was examined by immunostaining. Functional analysis of DN was performed by measuring extracellular dopamine levels under basal and glutamate-stimulated conditions. In addition, expression of molecules involved in dopamine homeostasis was examined by quantitative real-time polymerase chain reaction and immunostaining. Statistical analysis was performed using two-tailed Student’s t-tests.ResultsCompared with Ctrl-SHED, DS-SHED showed decreased expression of nestin, a neural stem-cell marker. Further, DS-SHED differentiated into DN (DS-DN) exhibiting decreased neurite outgrowth and branching compared with Ctrl-DN. In addition, DS-DN dopamine secretion was lower than Ctrl-DN dopamine secretion. Moreover, aberrant expression of molecules involved in dopaminergic homeostasis was observed in DS-DN.ConclusionsOur results suggest that there was developmental abnormality and DN malfunction in the DS-SHED donor in this study. In the future, to clarify the detailed mechanism of dopamine-signal abnormality due to DN developmental and functional abnormalities in DS, it is necessary to increase the number of patients for analysis. Non-invasively harvested SHED may be very useful in the analysis of DS pathology.Electronic supplementary materialThe online version of this article (10.1186/s12883-018-1140-2) contains supplementary material, which is available to authorized users.

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“…Glutamatergic neurons play critical roles in controlling cognitive, emotion, language, and motor function 2, 3 . Dysfunction of cortical glutamatergic neurons may be relevant to neurological diseases, such as Alzheimer’s disease 4 and Down syndrome 5, 6 . Availability of glutamatergic neurons in vitro may represent cell-based strategies for transplantation therapy and etiology studies.…”

Section: Introductionmentioning

confidence: 99%

Enhanced derivation of human pluripotent stem cell-derived cortical glutamatergic neurons by a small molecule

Cao

Chen

et al. 2017

Sci Rep

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Human pluripotent stem cells (hPSCs) play important role in studying the function of human glutamatergic neurons and related disease pathogenesis. However, the current hPSC-derived cortical system produced a significant number of inhibitory GABAergic neurons that reduced the purity of excitatory neurons. In this study, we established a robust hPSC-derived cortical neurogenesis system by applying the SHH inhibitor cyclopamine. Cyclopamine specified the dorsal cortical fate in a dose-dependent manner and enhanced the generation of cortical glutamatergic neurons, expressing PAX6, TBR1, TBR2, CTIP2, SATB2, and vesicular glutamate transporters (vGLUT). In contrast, the ventral patterning was inhibited and the GABAergic neurons were significantly reduced to 12% with the treatment of cyclopamine. In addition, we applied our current method to generate trisomy 21 iPSC-derived glutamatergic neurons that showed a robust reduction of vesicular glutamate transporters in the glutamatergic neurons with trisomy 21, revealing the developmental deficits in cortical glutamatergic neurons. Our method enriched the generation of cortical glutamatergic neurons which may facilitate the study of human neurological diseases and cell therapy.

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Reduced cortical neurotransmitter receptor complex levels in fetal Down syndrome brain

Cited by 11 publications

References 68 publications

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

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

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

Enhanced derivation of human pluripotent stem cell-derived cortical glutamatergic neurons by a small molecule

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