Diversity and development of local inhibitory and excitatory neurons associated with dopaminergic nuclei

Morello, Francesca; Partanen, Juha

doi:10.1016/j.febslet.2015.10.001

Cited by 27 publications

(19 citation statements)

References 131 publications

(209 reference statements)

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“…Thus, we next investigated the cellular composition of DAC3.0 MOs. We found that both GABAergic and mDA neurons are intimately colocated in most of the rosettes (Figure A), like in midbrain, where GABAergic neurons closely interact with mDA neurons in the substantia nigra, ventral tegmental area, and rostromedial tegmental nucleus . In contrast, DAC0 MOs (0 μM CHIR99021) and NS‐MOs (0.8 μM CHIR99021) exhibited heterogeneous distribution of GABAergic neurons.…”

Section: Resultsmentioning

confidence: 80%

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Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

et al. 2020

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Recent studies have demonstrated the generation of midbrain-like organoids (MOs) from human pluripotent stem cells. However, the low efficiency of MO generation and the relatively immature and heterogeneous structures of the MOs hinder the translation of these organoids from the bench to the clinic. Here we describe the robust generation of MOs with homogeneous distribution of midbrain dopaminergic (mDA) neurons. Our MOs contain not only mDA neurons but also other neuronal subtypes as well as functional glial cells, including astrocytes and oligodendrocytes. Furthermore, our MOs exhibit mDA neuron-specific cell death upon treatment with 1-methyl-4-phenyl-1,-2,3,6-tetrahydropyridine, indicating that MOs could be a proper human model system for studying the in vivo pathology of Parkinson's disease (PD). Our optimized conditions for producing homogeneous and mature MOs might provide an advanced patientspecific platform for in vitro disease modeling as well as for drug screening for PD.

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Section: Resultsmentioning

confidence: 80%

“…Midbrain contains not only mDA neurons, a functional cell type representative of the midbrain, but also several other cell types, such as different neuronal subtypes, astrocytes, and oligodendrocytes, which exert roles in maintaining the functional homeostasis of the midbrain . Thus, we next investigated the cellular composition of DAC3.0 MOs.…”

Section: Resultsmentioning

confidence: 99%

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

et al. 2020

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“…Function of these monoaminergic pathways is controlled by inhibitory and excitatory neurons, including important populations residing locally within the monoaminergic nuclei as well as in the adjacent midbrain and anterior hindbrain (Russo and Nestler, 2013;Lammel et al, 2014;Proulx et al, 2014;Morello and Partanen, 2015). Dysfunction of monoaminergic circuits is thought to lead to a multitude of psychiatric and neurophysiological disorders, such as schizophrenia, depression, addiction and Parkinson's disease.…”

Section: Introductionmentioning

confidence: 99%

Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei

et al. 2015

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Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared with the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral rhombomere 1, where the postmitotic selector genes Tal1, Gata2 and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in excessive numbers. Together, our results uncover developmental regulatory mechanisms, molecular characteristics, and heterogeneity of central regulators of monoaminergic circuits.

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“…For α-HBCD, glutamate significantly decreased following mid- and high-dose exposures. The contribution of glutamate to synaptic transmission, plasticity, and development is well established (Morello and Partanen 2015). For γ-HBCD, phenylalanine decreased significantly in both γ-HBCD dose groups.…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolomic Profiles in Neonatal Mice following Oral Brominated Flame Retardant Exposures to Hexabromocyclododecane (HBCD) Alpha, Gamma, and Commercial Mixture

Szabo

Pathmasiri

Sumner

et al. 2017

Environ Health Perspect

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Background:Hexabromocyclododecane (HBCD) is a high production volume brominated flame retardant added to building insulation foams, electronics, and textiles. HBCD is a commercial mixture (CM-HBCD) composed of three main stereoisomers: α-HBCD (10%), β-HBCD (10%), and γ-HBCD (80%). A shift from the dominant stereoisomer γ-HBCD to α-HBCD is detected in humans and wildlife.Objectives:Considering CM-HBCD has been implicated in neurodevelopment and endocrine disruption, with expected metabolism perturbations, we performed metabolomics on mice serum obtained during a window-of-developmental neurotoxicity to draw correlations between early-life exposures and developmental outcomes and to predict health risks.Methods:Six female C57BL/6 mice at postnatal day (PND) 10 were administered a single gavage dose of α-, γ-, or CM-HBCD at 3, 10, and 30 mg/kg. Nuclear magnetic resonance metabolomics was used to analyze 60 μL serum aliquots of blood collected 4 days post-oral exposure.Results:Infantile mice exposed to α-, γ-, or CM-HBCD demonstrated differences in endogenous metabolites by treatment and dose groups, including metabolites involved in glycolysis, gluconeogenesis, lipid metabolism, citric acid cycle, and neurodevelopment. Ketone bodies, 3-hydroxybutyrate, and acetoacetate, were nonstatistically elevated, when compared with mean control levels, in all treatment and dose groups, while glucose, pyruvate, and alanine varied. Acetoacetate was significantly increased in the 10 mg/kg α-HBCD and was nonsignificantly decreased with CM-HBCD. A third ketone body, acetone, was significantly lower in the 30 mg/kg α-HBCD group with significant increases in pyruvate at the same treatment and dose group. Metabolites significant in differentiating treatment and dose groups were also identified, including decreases in amino acids glutamate (excitatory neurotransmitter in learning and memory) and phenylalanine (neurotransmitter precursor) after α-HBCD and γ-HBCD exposure, respectively.Conclusions:We demonstrated that 4 days following a single neonatal oral exposure to α-, γ-, and CM-HBCD resulted in different serum metabolomic profiles, indicating stereoisomer- and mixture-specific effects and possible mechanisms of action.Citation:Szabo DT, Pathmasiri W, Sumner S, Birnbaum LS. 2017. Serum metabolomic profiles in neonatal mice following oral brominated flame retardant exposures to hexabromocyclododecane (HBCD) alpha, gamma, and commercial mixture. Environ Health Perspect 125:651–659; http://dx.doi.org/10.1289/EHP242

show abstract

Diversity and development of local inhibitory and excitatory neurons associated with dopaminergic nuclei

Cited by 27 publications

References 131 publications

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

Generation of homogeneous midbrain organoids with in vivo-like cellular composition facilitates neurotoxin-based Parkinson's disease modeling

Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei

Serum Metabolomic Profiles in Neonatal Mice following Oral Brominated Flame Retardant Exposures to Hexabromocyclododecane (HBCD) Alpha, Gamma, and Commercial Mixture

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