scholarly journals Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake

2021 ◽  
Author(s):  
Riccardo Melani ◽  
Nicolas Xavier Tritsch
Keyword(s):  
Gaba Receptors ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Gaba Uptake ◽  
Target Cells ◽  
Vesicular Release ◽  
Gaba Synthesis ◽  
Midbrain Dopamine

Dopamine (DA)-releasing neurons in the substantia nigra pars compacta (SNcDA) inhibit target cells in the striatum through postsynaptic activation of γ-aminobutyric acid (GABA) receptors. However, the molecular mechanisms responsible for GABAergic signaling remain unclear, as SNcDA neurons lack enzymes typically required to produce GABA or package it into synaptic vesicles. Here we show that aldehyde dehydrogenase 1a1 (Aldh1a1), an enzyme proposed to function as a GABA synthetic enzyme in SNcDA neurons does not produce GABA for synaptic transmission. Instead, we demonstrate that SNcDA axons obtain GABA exclusively through presynaptic uptake using the membrane GABA transporter Gat1 (encoded by Slc6a1). GABA is then packaged for vesicular release using the vesicular monoamine transporter Vmat2. Our data therefore show that presynaptic transmitter recycling can substitute for de novo GABA synthesis and that Vmat2 contributes to vesicular GABA transport, expanding the range of molecular mechanisms available to neurons to support inhibitory synaptic communication.

scholarly journals Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Nicolas X Tritsch ◽  
Won-Jong Oh ◽  
Chenghua Gu ◽  
Bernardo L Sabatini
Keyword(s):  
Dopaminergic Neurons ◽  
De Novo ◽  
Dopamine Neurons ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
Dependent Manner ◽  
Gaba Transporters ◽  
Midbrain Dopamine ◽  
Nigrostriatal Dopamine Neurons ◽  
Midbrain Dopamine Neurons

Synaptic transmission between midbrain dopamine neurons and target neurons in the striatum is essential for the selection and reinforcement of movements. Recent evidence indicates that nigrostriatal dopamine neurons inhibit striatal projection neurons by releasing a neurotransmitter that activates GABAA receptors. Here, we demonstrate that this phenomenon extends to mesolimbic afferents, and confirm that the released neurotransmitter is GABA. However, the GABA synthetic enzymes GAD65 and GAD67 are not detected in midbrain dopamine neurons. Instead, these cells express the membrane GABA transporters mGAT1 (Slc6a1) and mGAT4 (Slc6a11) and inhibition of these transporters prevents GABA co-release. These findings therefore indicate that GABA co-release is a general feature of midbrain dopaminergic neurons that relies on GABA uptake from the extracellular milieu as opposed to de novo synthesis. This atypical mechanism may confer dopaminergic neurons the flexibility to differentially control GABAergic transmission in a target-dependent manner across their extensive axonal arbors.

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

2021 ◽  
Vol 118 (40) ◽  
pp. e2111069118
Author(s):  
Theodoros Tsetsenis ◽  
Julia K. Badyna ◽  
Julianne A. Wilson ◽  
Xiaowen Zhang ◽  
Elizabeth N. Krizman ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Dorsal Hippocampus ◽  
Memory Formation ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Aversive Learning ◽  
Contextual Fear ◽  
Dopaminergic Transmission ◽  
Midbrain Dopaminergic Neurons ◽  
Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

scholarly journals Neurexins Regulate GABA Co-release by Dopamine Neurons

2021 ◽  
Author(s):  
Charles Ducrot ◽  
Gregory de Carvalho ◽  
Benoit Delignat-Lavaud ◽  
Constantin Delmas ◽  
Nicolas Giguere ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Dopamine Neurons ◽  
Electrophysiological Recording ◽  
Conditional Deletion ◽  
Synaptic Cell Adhesion Molecules ◽  
Midbrain Dopamine ◽  
Neuron Terminals ◽  
Reduced Rate ◽  
Activity Dependent ◽  
Da Release

Midbrain dopamine (DA) neurons are key regulators of basal ganglia functions. The axonal domain of these neurons is highly complex, with a large subset of non-synaptic release sites and a smaller subset of synaptic terminals from which glutamate or GABA are released. The molecular mechanisms regulating the connectivity of DA neurons and their neurochemical identity are unknown. Here we tested the hypothesis that the trans-synaptic cell adhesion molecules neurexins (Nrxns) regulate DA neuron neurotransmission. Conditional deletion of all Nrxns in DA neurons (DAT::Nrxns KO) revealed that loss of Nrxns does not impair the basic development and ultrastructural characteristics of DA neuron terminals. However, loss of Nrxns caused an impairment of DA transmission revealed as a reduced rate of DA reuptake following activity-dependent DA release, decreased DA transporter levels, increased vesicular monoamine transporter expression and impaired amphetamine-induced locomotor activity. Strikingly, electrophysiological recording revealed an increase of GABA co-release from DA neuron axons in the striatum of the KO mice. These findings reveal that Nrxns act as key regulators of DA neuron connectivity and DA-mediated functions.

scholarly journals Molecular Mechanisms Underlying Synaptic and Axon Degeneration in Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Nolwazi Z. Gcwensa ◽  
Drèson L. Russell ◽  
Rita M. Cowell ◽  
Laura A. Volpicelli-Daley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Mechanisms ◽  
Disease Onset ◽  
Neuronal Cell ◽  
Rem Sleep Behavior Disorder ◽  
Dopamine Neurons ◽  
Neuronal Cell Body ◽  
Substantia Nigra Pars Compacta ◽  
Cognitive Changes

Parkinson’s disease (PD) is a progressive neurodegenerative disease that impairs movement as well as causing multiple other symptoms such as autonomic dysfunction, rapid eye movement (REM) sleep behavior disorder, hyposmia, and cognitive changes. Loss of dopamine neurons in the substantia nigra pars compacta (SNc) and loss of dopamine terminals in the striatum contribute to characteristic motor features. Although therapies ease the symptoms of PD, there are no treatments to slow its progression. Accumulating evidence suggests that synaptic impairments and axonal degeneration precede neuronal cell body loss. Early synaptic changes may be a target to prevent disease onset and slow progression. Imaging of PD patients with radioligands, post-mortem pathologic studies in sporadic PD patients, and animal models of PD demonstrate abnormalities in presynaptic terminals as well as postsynaptic dendritic spines. Dopaminergic and excitatory synapses are substantially reduced in PD, and whether other neuronal subtypes show synaptic defects remains relatively unexplored. Genetic studies implicate several genes that play a role at the synapse, providing additional support for synaptic dysfunction in PD. In this review article we: (1) provide evidence for synaptic defects occurring in PD before neuron death; (2) describe the main genes implicated in PD that could contribute to synapse dysfunction; and (3) show correlations between the expression of Snca mRNA and mouse homologs of PD GWAS genes demonstrating selective enrichment of Snca and synaptic genes in dopaminergic, excitatory and cholinergic neurons. Altogether, these findings highlight the need for novel therapeutics targeting the synapse and suggest that future studies should explore the roles for PD-implicated genes across multiple neuron types and circuits.

Differential Modulation by Nicotine of Substantia Nigra Versus Ventral Tegmental Area Dopamine Neurons

2007 ◽  
Vol 98 (6) ◽  
pp. 3388-3396 ◽  
Author(s):  
J. Russel Keath ◽  
Michael P. Iacoviello ◽  
Lindy E. Barrett ◽  
Huibert D. Mansvelder ◽  
Daniel S. McGehee
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Dorsal Striatum ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Synaptic Modulation ◽  
Afferent Projections ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Da Release

Midbrain dopamine (DA) neurons are found in two nuclei, the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The SNc dopaminergic projections to the dorsal striatum are involved in voluntary movement and habit learning, whereas the VTA projections to the ventral striatum contribute to reward and motivation. Nicotine induces profound DA release from VTA dopamine neurons but substantially less from the SNc. Nicotinic acetylcholine receptor (nAChR) expression differs between these nuclei, but it is unknown whether there are differences in nAChR expression on the afferent projections to these nuclei. Here we have compared the nicotinic modulation of excitatory and inhibitory synaptic inputs to VTA and SNc dopamine neurons. Although nicotine enhances both the excitatory and inhibitory drive to SNc DA cells with response magnitudes similar to those seen in the VTA, the prevalence of these responses in SNc is much lower. We also found that a mixture of nAChR subtypes underlies the synaptic modulation in SNc, further distinguishing this nucleus from the VTA, where α7 nAChRs enhance glutamate inputs and non-α7 receptors enhance GABA inputs. Finally, we compared the nicotine sensitivity of DA neurons in these two nuclei and found larger response magnitudes in VTA relative to SNc. Thus the observed differences in nicotine-induced DA release from VTA and SNc are likely due to differences in nAChR expression on the afferent inputs as well as on the DA neurons themselves. This may explain why nicotine has a greater effect on behaviors associated with the VTA than the SNc.

scholarly journals Spatial RNA Sequencing Identifies Robust Markers of Vulnerable and Resistant Human Midbrain Dopamine Neurons and Their Expression in Parkinson’s Disease

2021 ◽  
Vol 14 ◽  
Author(s):  
Julio Aguila ◽  
Shangli Cheng ◽  
Nigel Kee ◽  
Ming Cao ◽  
Menghan Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Sample ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Minimal Sample ◽  
Differential Vulnerability ◽  
Minimal Sample Size ◽  
Midbrain Dopamine ◽  
Small Sample Sizes

Defining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understanding their differential vulnerability in Parkinson’s Disease (PD). Here, we determine transcriptomes of human SNc and VTA dopamine neurons using LCM-seq on a large sample cohort. We apply a bootstrapping strategy as sample input to DESeq2 and identify 33 stably differentially expressed genes (DEGs) between these two subpopulations. We also compute a minimal sample size for identification of stable DEGs, which highlights why previous reported profiles from small sample sizes display extensive variability. Network analysis reveal gene interactions unique to each subpopulation and highlight differences in regulation of mitochondrial stability, apoptosis, neuronal survival, cytoskeleton regulation, extracellular matrix modulation as well as synapse integrity, which could explain the relative resilience of VTA dopamine neurons. Analysis of PD tissues showed that while identified stable DEGs can distinguish the subpopulations also in disease, the SNc markers SLIT1 and ATP2A3 were down-regulated and thus appears to be biomarkers of disease. In summary, our study identifies human SNc and VTA marker profiles, which will be instrumental for studies aiming to modulate dopamine neuron resilience and to validate cell identity of stem cell-derived dopamine neurons.

Cordycepin Exerts Neuroprotective Effects via an Anti-Apoptotic Mechanism based on the Mitochondrial Pathway in a Rotenone-Induced Parkinsonism Rat Model

2019 ◽  
Vol 18 (8) ◽  
pp. 609-620 ◽  
Author(s):  
Xin Jiang ◽  
Pei-Chen Tang ◽  
Qin Chen ◽  
Xin Zhang ◽  
Yi-Yun Fan ◽  
...  
Keyword(s):  
Rat Model ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Neuroprotective Effects ◽  
Cyt C

Background: Cordycepin (Cor), one of the major bioactive components of the traditional Chinese medicine Cordyceps militaris, has been used in clinical practice for several years. However, its neuroprotective effect remains unknown. Aim: The purpose of the study was to evaluate the neuroprotective effects of Cor using a rotenoneinduced Parkinson’s Disease (PD) rat model and to delineate the possible associated molecular mechanisms. Methods: In vivo, behavioural tests were performed based on the 10-point scale and grid tests. Levels of dopamine and its metabolites in the striatum and the numbers of TH-positive neurons in the Substantia Nigra pars compacta (SNpc) were investigated by high-performance liquid chromatography with electrochemical detection and immunohistochemical staining, respectively. In vitro, cell apoptosis rates and Mitochondrial Membrane Potential (MMP) were analysed by flow cytometry and the mRNA and protein levels of Bax, Bcl-2, Bcl-xL, Cytochrome c (Cyt-c), and caspase-3 were determined by quantitative real-time PCR and western blotting. Results: Showed that Cor significantly improved dyskinesia, increased the numbers of TH-positive neurons in the SNpc, and maintained levels of dopamine and its metabolites in the striatum in rotenone- induced PD rats. We also found that apoptosis was suppressed and the loss of MMP was reversed with Cor treatment. Furthermore, Cor markedly down-regulated the expression of Bax, upregulated Bcl-2 and Bcl-xL, inhibited the activation of caspase-3, and decreased the release of Cyt-c from the mitochondria to the cytoplasm, as compared to those in the rotenone-treated group. Conclusion: Therefore, Cor protected dopamine neurons against rotenone-induced apoptosis by improving mitochondrial dysfunction in a PD model, demonstrating its therapeutic potential for this disease.

scholarly journals Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

2019 ◽  
Author(s):  
Michelle Kokkinou ◽  
Elaine E. Irvine ◽  
David R. Bonsall ◽  
Sridhar Natesan ◽  
Lisa A. Wells ◽  
...  
Keyword(s):  
Locomotor Activity ◽  
Molecular Mechanisms ◽  
Imaging Study ◽  
Dopamine Neurons ◽  
Striatal Dopamine ◽  
Pharmacological Intervention ◽  
Dopamine Synthesis ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

ABSTRACTPatients 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, P<0.001) 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.

scholarly journals LCM-seq identifies robust markers of vulnerable and resistant human midbrain dopamine neurons

2020 ◽  
Author(s):  
Julio Aguila ◽  
Shangli Cheng ◽  
Nigel Kee ◽  
Ming Cao ◽  
Qiaolin Deng ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Small Sample ◽  
Dopamine Neurons ◽  
Differentially Expressed ◽  
Substantia Nigra Pars Compacta ◽  
Cohort Size ◽  
Neuron Populations ◽  
Extensive Collection ◽  
Midbrain Dopamine ◽  
Small Sample Sizes

ABSTRACTDefining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons in human is critical to understanding their differential vulnerability in Parkinson Disease. However, reported marker profiles for these neuron populations are derived predominantly from rodents, utilize small sample sizes and display extensive variability between studies. Here, we map selective expression profiles of dopamine neurons in an extensive collection of human SNc and VTA using laser capture microdissection coupled with Smart-seq2 RNA sequencing (LCM-seq). By applying a bootstrapping strategy as sample input to DESeq2, we identify 33 differentially expressed SNc- or VTA-specific markers and we also compute the minimal cohort size required to identify differentially expressed genes (DEGs) that are concordant regardless of cohort size. Among the identified DEGs, ZCCHC12, CDH13 and SERPINE2, are minimally required to distinguish SNc or VTA dopamine neurons in both human and mouse. In summary, our study identifies novel markers, besides previously identified ones, which will be instrumentsal for future studies aiming to modulate dopamine neuron resilience as well as validate cell identity of stem cell-derived dopamine neurons.

scholarly journals Spatial transcriptomics and in silico random pooling identify novel markers of vulnerable and resistant midbrain dopamine neurons

2018 ◽  
Author(s):  
Julio Aguila ◽  
Shangli Cheng ◽  
Nigel Kee ◽  
Ming Cao ◽  
Qiaolin Deng ◽  
...  
Keyword(s):  
Small Sample ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
The Novel ◽  
Transcriptional Profiles ◽  
Neuron Populations ◽  
Differential Vulnerability ◽  
Midbrain Dopamine ◽  
High Utility ◽  
Small Sample Sizes

SUMMARYDefining transcriptional profiles of substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) dopamine neurons is critical to understand their differential vulnerability in Parkinson’s disease. However, reported transcriptional profiles for these neuron populations rely on studies in rodents and display extensive variability across small sample sizes. Here, we use laser capture microdissection coupled with RNA sequencing to analyze single isolated SNc and VTA dopamine neurons in a large human cohort. By applying a unique iterative random pooling algorithm, with high utility to resolve differences across any two populations, we reveal 33 dopamine population-specific markers We also define the minimal cohort size required to identify these stably differentially expressed genes, explaining inconsistent results from previous studies. Finally, we identify human transcripts, including ZCCHC12, CDH13 and SERPINE2, that faithfully classify SNc or VTA dopamine neurons also in the mouse. The novel markers identified will be vital for future studies aiming to validate the identity of stem cell-derived dopamine neurons or to induce dopamine neuron resilience.

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