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.

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 Dopamine neuron-derived IGF-1 controls dopamine neuron firing, skill learning, and exploration

2019 ◽  
Vol 116 (9) ◽  
pp. 3817-3826 ◽  
Author(s):  
Alessandro Pristerà ◽  
Craig Blomeley ◽  
Emanuel Lopes ◽  
Sarah Threlfell ◽  
Elisa Merlini ◽  
...  
Keyword(s):  
Cognitive Processes ◽  
Skill Learning ◽  
Dopamine Neuron ◽  
Dopamine Neurons ◽  
Neuron Firing ◽  
Adult Mice ◽  
Conditional Deletion ◽  
Dopamine Content ◽  
Midbrain Dopamine

Midbrain dopamine neurons, which can be regulated by neuropeptides and hormones, play a fundamental role in controlling cognitive processes, reward mechanisms, and motor functions. The hormonal actions of insulin-like growth factor 1 (IGF-1) produced by the liver have been well described, but the role of neuronally derived IGF-1 remains largely unexplored. We discovered that dopamine neurons secrete IGF-1 from the cell bodies following depolarization, and that IGF-1 controls release of dopamine in the ventral midbrain. In addition, conditional deletion of dopamine neuron-derived IGF-1 in adult mice leads to decrease of dopamine content in the striatum and deficits in dopamine neuron firing and causes reduced spontaneous locomotion and impairments in explorative and learning behaviors. These data identify that dopamine neuron-derived IGF-1 acts as a regulator of dopamine neurons and regulates dopamine-mediated behaviors.

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 Basal forebrain mediates prosocial behavior via disinhibition of midbrain dopamine neurons

2021 ◽  
Vol 118 (7) ◽  
pp. e2019295118
Author(s):  
Jun Wang ◽  
Jie Li ◽  
Qian Yang ◽  
Ya-Kai Xie ◽  
Ya-Lan Wen ◽  
...  
Keyword(s):  
Social Interaction ◽  
Prosocial Behavior ◽  
Basal Forebrain ◽  
Social Preference ◽  
Dopamine Neurons ◽  
Inhibitory Neurons ◽  
Axon Terminals ◽  
Midbrain Dopamine ◽  
Da Release

Sociability is fundamental for our daily life and is compromised in major neuropsychiatric disorders. However, the neuronal circuit mechanisms underlying prosocial behavior are still elusive. Here we identify a causal role of the basal forebrain (BF) in the control of prosocial behavior via inhibitory projections that disinhibit the midbrain ventral tegmental area (VTA) dopamine (DA) neurons. Specifically, BF somatostatin-positive (SST) inhibitory neurons were robustly activated during social interaction. Optogenetic inhibition of these neurons in BF or their axon terminals in the VTA largely abolished social preference. Electrophysiological examinations further revealed that SST neurons predominantly targeted VTA GABA neurons rather than DA neurons. Consistently, optical inhibition of SST neuron axon terminals in the VTA decreased DA release in the nucleus accumbens during social interaction, confirming a disinhibitory action. These data reveal a previously unappreciated function of the BF in prosocial behavior through a disinhibitory circuitry connected to the brain’s reward system.

scholarly journals The calcium sensor synaptotagmin-1 is critical for phasic axonal dopamine release in the striatum and mesencephalon, but is dispensable for basic motor behaviors in mice

2021 ◽  
Author(s):  
Benoit Delignat-Lavaud ◽  
Jana Kano ◽  
Charles Ducrot ◽  
Ian Masse ◽  
Sriparna Mukherjee ◽  
...  
Keyword(s):  
Calcium Sensor ◽  
Motor Tasks ◽  
Motor Functions ◽  
Motor Behaviors ◽  
Basal Tone ◽  
Synaptotagmin 1 ◽  
Midbrain Dopamine ◽  
Motivated Behaviors ◽  
Activity Dependent ◽  
Da Release

Midbrain dopamine (DA) neurons, a population of cells that are critical for motor control, motivated behaviors and cognition, release DA via an exocytotic mechanism from both their axonal terminals and their somatodendritic (STD) compartment. In Parkinson's disease (PD), it is striking that motor dysfunctions only become apparent after extensive loss of DA innervation. Although it has been hypothesized that this resilience is due to the ability of many motor behaviors to be sustained through a basal tone of DA and diffuse transmission, experimental evidence for this is limited. Here we conditionally deleted the calcium sensor synaptotagmin-1 (Syt1) in DA neurons (cKODA mice) to abrogate most activity-dependent axonal DA release in the striatum and mesencephalon, leaving STD DA release intact. Strikingly, Syt1 cKODA mice showed intact performance in multiple unconditioned DA-dependent motor tasks, suggesting that activity-dependent DA release is dispensable for such basic motor functions. Basal extracellular levels of DA in the striatum were unchanged, suggesting that a basal tone of extracellular DA is sufficient to sustain basic movement. We also found multiple adaptations in the DA system of cKODA mice, similar to those happening at early stages of PD. Taken together, our findings reveal the striking resilience of DA-dependent motor functions in the context of a near-abolition of phasic DA release, shedding new light on why extensive loss of DA innervation is required to reveal motor dysfunctions in PD.

scholarly journals A conserved nuclear export complex coordinates transcripts for dopaminergic synaptogenesis and neuronal surviva

2018 ◽  
Author(s):  
Celine I. Maeder ◽  
Jae-Ick Kim ◽  
Konstantin Kaganovsky ◽  
Ao Shen ◽  
Qin Li ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Dopamine Neurons ◽  
List Type ◽  
Messenger Rnas ◽  
Knock Out ◽  
Forward Genetic Screens ◽  
Synapse Maintenance ◽  
Activity Dependent

SummarySynaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export Complex (THOC) as master regulator of presynapse development in C.elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are trapped in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses and compromised dopamine function. cAMP-responsive element binding protein (CREB) interacts with THOC to mark activity-dependent transcripts for efficient nuclear export. Deletion of the THOC subunit Thoc5 in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the Substantia Nigra compacta (SNc). These cellular defects lead to abrogated dopamine release, ataxia and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for synapse development and neuronal survival.HighlightsDopaminergic presynapses are severely impaired in thoc mutant worms and miceTHOC specifically controls the nuclear export of synaptic transcriptsCREB recruits THOC onto activity-dependent synaptic transcripts for efficient exportDopamine neurons in the SNc degenerate upon conditional knock-out of thoc5

scholarly journals Noncoding RNAs and Midbrain DA Neurons: Novel Molecular Mechanisms and Therapeutic Targets in Health and Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1269
Author(s):  
Emilia Pascale ◽  
Giuseppina Divisato ◽  
Renata Palladino ◽  
Margherita Auriemma ◽  
Edward Faustine Ngalya ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Noncoding Rnas ◽  
Physiological Role ◽  
Dopamine Neurons ◽  
Neuron Development ◽  
Dopaminergic Neurodegeneration ◽  
Midbrain Dopamine ◽  
Altered Proteins ◽  
Midbrain Dopamine Neurons

Midbrain dopamine neurons have crucial functions in motor and emotional control and their degeneration leads to several neurological dysfunctions such as Parkinson’s disease, addiction, depression, schizophrenia, and others. Despite advances in the understanding of specific altered proteins and coding genes, little is known about cumulative changes in the transcriptional landscape of noncoding genes in midbrain dopamine neurons. Noncoding RNAs—specifically microRNAs and long noncoding RNAs—are emerging as crucial post-transcriptional regulators of gene expression in the brain. The identification of noncoding RNA networks underlying all stages of dopamine neuron development and plasticity is an essential step to deeply understand their physiological role and also their involvement in the etiology of dopaminergic diseases. Here, we provide an update about noncoding RNAs involved in dopaminergic development and metabolism, and the related evidence of these biomolecules for applications in potential treatments for dopaminergic neurodegeneration.

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.

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