Human Pluripotent Stem Cell-derived Medium Spiny Neurons (hMSNs) Exhibit Acute and Chronic Responses to Dopamine
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE195492 | GEO | 2022/04/20
REPOSITORIES: GEO
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Project description:Human Pluripotent Stem Cell-derived Medium Spiny Neurons (hMSNs) Exhibit Acute and Chronic Responses to Dopamine
| PRJNA800804 | ENA
Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease. To profile the cell-type-specific responses of striatal spiny projection neurons (SPNs) to striatal dopamine depletion, we conducted TRAP analysis of the two major classes of these neurons: dSPNs that express the dopamine receptor 1a (Drd1a), and iSPNs that express the dopamine receptor 2 (Drd2). To disrupt dopamine innervation to both of these SPN populations that reside in the striatum, we injected the neurotoxin 6-hydroxydopamine (6-OHDA), unilaterally, in the medial forebrain bundle (MFB) in hemizygous Drd1-TRAP and Drd2-TRAP adult (9-14 weeks) male mice (kept on a C57BL/6J genetic background). This lesion procedure causes nigral dopamine cell death within a few days, along with a widespread and near-complete loss of dopaminergic innervation to the entire dorsal striatum on one side of the brain (a hemiparkinsonian model). We first examined the effects of dopamine depletion alone, compared to a mock lesion (ascorbate / saline injected). We then examined the effects of chronic levodopa treatment upon the molecular profiles of dopamine- depleted dSPNs and iSPNs, with two dose regimens. The ‘high-dose’ L-DOPA regimen (3 mg/kg on days 1-3, followed by 6 mg/kg on days 4-9) was expected to induce severe dyskinesia in all MFB-lesioned mice. The low-dose L-DOPA regimen (1 mg/kg on days 1-3, followed by 2 mg/kg on days 4-9) was expected to reverse limb use asymmetry without causing conspicuous dyskinesias. To equalize the effects of stress and handling across all groups, including control groups, all mice were equally handled and thus received saline injections when not receiving levodopa injections. Each treatment group contained 7-10 replicates. TRAP-purified mRNAs from either Drd1a- or Drd2-expressing SPNs were reverse-transcribed, amplified, and used to interrogate Affymetrix 430_2.0 GeneChip microarrays.
2014-03-03 | E-GEOD-55096 | biostudies-arrayexpress
Project description:Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.
2021-02-16 | GSE138802 | GEO
Project description:The dopamine transporter facilitates dopamine reuptake from the extracellular space to terminate neurotransmission. The transporter belongs to the neurotransmitter:sodium symporter family, which includes transporters for serotonin, norepinephrine, and GABA that utilize the Na+ gradient to drive the uptake of substrate. Decades ago, it was shown that the serotonin transporter also antiports K+, but investigations of K+-coupled transport in other neurotransmitter:sodium symporters have been inconclusive. Here, we show that ligand binding to the drosophila- and human dopamine transporters are inhibited by K+, and the conformational dynamics of the drosophila dopamine transporter in K+ are divergent from the apo- and Na+-states. Furthermore, we found that K+ increased dopamine uptake by the drosophila dopamine transporter in liposomes, and visualized Na+ and K+ fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K+ on other transporters in this pharmacologically important family.
2022-05-20 | PXD032663 | Pride
Project description:Dopamine signaling in the adult ventral forebrain regulates behavior, stress response, and memory formation and in neurodevelopment regulates neural differentiation and cell migration. Excessive dopamine levels including due to cocaine use both in utero and in adults could lead to long-term adverse consequences. The mechanisms underlying both homeostatic and pathological changes remain unclear, partly due to the diverse cellular responses elicited by dopamine and the reliance on animal models that exhibit species-specific differences in dopamine signaling. To address these limitations, 3-D cerebral organoids have emerged as human-derived models, recapitulating salient features of human cell signaling and neurodevelopment. Organoids have demonstrated responsiveness to external stimuli, including substances of abuse, making them valuable investigative models. In this study we utilize the Xiang-Tanaka ventral forebrain organoid model and characterize their response to acute and chronic dopamine or cocaine exposure. The findings revealed a robust immune response, novel response pathways, and a potential critical role for reactive oxygen species (ROS) in the developing ventral forebrain. These results highlight the potential of cerebral organoids as in vitro human models for studying complex biological processes in the brain.
2023-08-07 | GSE234767 | GEO
Project description:Dopamine signaling in the adult ventral forebrain regulates behavior, stress response, and memory formation and in neurodevelopment regulates neural differentiation and cell migration. Excessive dopamine levels including due to cocaine use both in utero and in adults could lead to long-term adverse consequences. The mechanisms underlying both homeostatic and pathological changes remain unclear, partly due to the diverse cellular responses elicited by dopamine and the reliance on animal models that exhibit species-specific differences in dopamine signaling. To address these limitations, 3-D cerebral organoids have emerged as human-derived models, recapitulating salient features of human cell signaling and neurodevelopment. Organoids have demonstrated responsiveness to external stimuli, including substances of abuse, making them valuable investigative models. In this study we utilize the Xiang-Tanaka ventral forebrain organoid model and characterize their response to acute and chronic dopamine or cocaine exposure. The findings revealed a robust immune response, novel response pathways, and a potential critical role for reactive oxygen species (ROS) in the developing ventral forebrain. These results highlight the potential of cerebral organoids as in vitro human models for studying complex biological processes in the brain.
2023-08-07 | GSE234766 | GEO
Project description:Dopaminylation, the covalent attachment of dopamine to the side chain of glutamine (Gln, Q) in proteins, has been identified as a class of posttranslational modification. Due to the limited number of substrates, the functions and underlying molecular mechanisms of dopaminylation are not fully characterized. Utilizing an alkyne-functionalized dopamine probe, we have developed a method to selectively enrich dopaminylated proteins in the whole-cell context. We identified 4133 proteins potentially modified with dopamine and validated the modification of histone H4 glutamine 27 by dopamine (H4Q27dop). H4Q27dop can inhibit cell proliferation through downregulating cyclin D1 gene CCND1 transcription, a classical well-known proliferation promoter. Our study provides a valuable resource of putative substrate proteins modified with dopamine and reveals a novel mechanism of dopamine regulating cell growth in a neuroblastoma cancer model.
2024-07-10 | GSE271454 | GEO
Project description:Transcriptomic responses to neurotransmitters contribute to the complex processes driving memory and addiction. Advances in both measurement methods and experimental models continue to improve our understanding of this regulatory layer. Here we focus on the experimental potential of stem cell derived neurons, currently the only ethical model that can be used in reductionist and experimentally perturbable studies of human cells. Prior work has focused on generating distinct cell types from human stem cells, and has also shown their utility in modeling development and cellular phenotypes related to neurodegeneration. Here we seek an understanding of how stem cell derived neural cultures respond to perturbations experienced during development and disease progression. This work profiles transcriptomic responses of human medium spiny neuron-like cells with three specific goals. We first characterize transcriptomic responses to dopamine and dopamine receptor agonists and antagonists presented in dosing patterns mimicking acute, chronic, and withdrawal regimens. We also assess transcriptomic responses to low and persistent tonic levels of dopamine, acetylcholine, and glutamate to better mimic the in vivo environment. Finally, we identify similar and distinct responses between hMSN-like cells derived from H9 and H1 stem cell lines, providing some context for the extent of variability these types of systems will likely pose for experimentalists. The results here suggest future optimizations of human stem cell derived neurons to increase their in vivo relevance and the biological insights that can be garnered from these models.
2023-07-06 | GSE236684 | GEO
Project description:HIV and Methamphetamine study - Translational Methamphetamine AIDS Research Center - Dopamine-regulated inflammatory biomarkers A digital transcript panel was custom-made based on Hs_NeuroPath_v1 (Nanostring) to accommodate dopamine-regulated inflammatory genes that were previously identified in vitro, and hypothesized to cluster HIV+ Methamphetamine users.
2024-07-31 | GSE273630 | GEO
Project description:Yapo2017- cAMP/PKA signalling in D1 dopamine receptor expressing medium-spiny neurons
This model is described in the article:
Detection of phasic dopamine
by D1 and D2 striatal medium spiny neurons.
Yapo C, Nair AG, Clement L, Castro
LR, Hellgren Kotaleski J, Vincent P.
J. Physiol. (Lond.) 2017 Aug; :
Abstract:
The phasic release of dopamine in the striatum determines
various aspects of reward and action selection, but the
dynamics of dopamine effect on intracellular signalling remains
poorly understood. We used genetically-encoded FRET biosensors
in striatal brain slices to quantify the effect of transient
dopamine on cAMP or PKA-dependent phosphorylation level, and
computational modelling to further explore the dynamics of this
signalling pathway. Medium-sized spiny neurons (MSNs), which
express either D1 or D2 dopamine receptors, responded to
dopamine by an increase or a decrease in cAMP, respectively.
Transient dopamine showed similar sub-micromolar efficacies on
cAMP in both D1 and D2 MSNs, thus challenging the commonly
accepted notion that dopamine efficacy is much higher on D2
than on D1 receptors. However, in D2 MSNs, the large decrease
in cAMP level triggered by transient dopamine did not translate
in a decrease in PKA-dependent phosphorylation level, owing to
the efficient inhibition of Protein Phosphatase 1 by DARPP-32.
Simulations further suggested that D2 MSNs can also operate in
a "tone-sensing" mode, allowing them to detect transient dips
in basal dopamine. Overall, our results show that D2 MSNs may
sense much more complex patterns of dopamine than previously
thought. This article is protected by copyright. All rights
reserved.
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2017-08-16 | MODEL1701170000 | BioModels