Mechanisms of dopamine quantal size regulation

Daniela, B. Pereira

doi:10.2741/4083

Cited by 20 publications

(19 citation statements)

References 226 publications

(371 reference statements)

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“…Genetic variations that affect DAT function hold great potential to change dopaminergic homeostasis by disturbing termination of dopamine signaling and the synthesisindependent supply of dopamine for vesicular storage (56,57). Consistently, SLC6A3, encoding DAT, has been a long-standing candidate gene in psychiatric diseases, such as bipolar disorder, schizophrenia, and ADHD (22,(58)(59)(60), but the reported effect sizes of associated common variants are small, as for most other genes, and this challenges deduction of potential disease relevant biological processes.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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Genetic factors are known to significantly contribute to the etiology of psychiatric diseases such as attention deficit hyperactivity disorder (ADHD) and autism spectrum and bipolar disorders, but the underlying molecular processes remain largely elusive. The dopamine transporter (DAT) has received continuous attention as a potential risk factor for psychiatric disease, as it is critical for dopamine homeostasis and serves as principal target for ADHD medications. Constrain metrics for the DAT-encoding gene solute carrier family 6 member 3 (SLC6A3) indicate that missense mutations are under strong negative selection, pointing to pathophysiological outcomes when DAT function is compromised. Here, we systematically characterized six rare genetic variants of DAT (I312F, T356M, D421N, A559V, E602G, and R615C) identified in patients with neuropsychiatric disorders. We evaluated dopamine uptake and ligand interactions, along with ion coordination and electrophysiological properties, to elucidate functional phenotypes, and applied Zn 2+ exposure and a substituted cysteineaccessibility approach to identify shared structural changes. Three variants (I312F, T356M, and D421N) exhibited impaired dopamine uptake associated with changes in ligand binding, ion coordination, and distinct conformational disturbances. Remarkably, we found that all three variants displayed gain-offunction electrophysiological phenotypes. I312F mediated an increased uncoupled anion conductance previously suggested to modulate neuronal excitability. T356M and D421N both mediated a cocaine-sensitive leakage of cations, which for T356M, was potentiated by Zn 2+ , concurrent with partial functional rescue. Collectively, our findings support that gain of disruptive functions due to missense mutations in SLC6A3 may be key to understanding how dopaminergic dyshomeostasis arises in heterozygous carriers.A substantial proportion of the disease etiology of common psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder, and schizophrenia is attributed genetic components (1). The underlying neurobiological mechanisms are not clear, but dopamine disturbances are believed to constitute a central component (2-7). The allelic spectrum of these dopamine-related disorders is rapidly expanding and comprises both common variants and rare structural or exonic mutations, including de novo variants (1,(8)(9)(10)(11)(12). Moreover, an interesting overlap in the genetic architecture of psychiatric disorders has been observed, and this pleiotrophy is seen for both common and rare variants (13)(14)(15)(16)(17)(18). Despite progress, much of the genetic component remains unaccounted for, and we also have the challenge ahead of translating most of the comprehensive genetic information into an understanding of underlying biological processes, and subsequently into clinically applicable knowledge. Rare variants may provide a unique handle for obtaining new disease insights as they are expected to h...

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Section: Discussionmentioning

confidence: 99%

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Herborg

Andreassen

Berlin

et al. 2018

Journal of Biological Chemistry

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“…Dopaminergic terminals were extensively colabeled for TH, DAT, and VMAT2, which are essential for the synthesis, recycling, and vesicular filling of dopamine (24). Moreover, CAST and Nrxn, which are involved in active zone formation and synaptic adhesion, respectively (6,25), accumulated on the presynaptic membrane at dopamine synapses and were expressed at levels comparable to conventional glutamatergic and GABAergic synapses.…”

Section: Discussionmentioning

confidence: 99%

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

Uchigashima

Ohtsuka

Kobayashi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

105

104

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Midbrain dopamine neurons project densely to the striatum and form so-called dopamine synapses on medium spiny neurons (MSNs), principal neurons in the striatum. Because dopamine receptors are widely expressed away from dopamine synapses, it remains unclear how dopamine synapses are involved in dopaminergic transmission. Here we demonstrate that dopamine synapses are contacts formed between dopaminergic presynaptic and GABAergic postsynaptic structures. The presynaptic structure expressed tyrosine hydroxylase, vesicular monoamine transporter-2, and plasmalemmal dopamine transporter, which are essential for dopamine synthesis, vesicular filling, and recycling, but was below the detection threshold for molecules involving GABA synthesis and vesicular filling or for GABA itself. In contrast, the postsynaptic structure of dopamine synapses expressed GABAergic molecules, including postsynaptic adhesion molecule neuroligin-2, postsynaptic scaffolding molecule gephyrin, and GABA A receptor α1, without any specific clustering of dopamine receptors. Of these, neuroligin-2 promoted presynaptic differentiation in axons of midbrain dopamine neurons and striatal GABAergic neurons in culture. After neuroligin-2 knockdown in the striatum, a significant decrease of dopamine synapses coupled with a reciprocal increase of GABAergic synapses was observed on MSN dendrites. This finding suggests that neuroligin-2 controls striatal synapse formation by giving competitive advantage to heterologous dopamine synapses over conventional GABAergic synapses. Considering that MSN dendrites are preferential targets of dopamine synapses and express high levels of dopamine receptors, dopamine synapse formation may serve to increase the specificity and potency of dopaminergic modulation of striatal outputs by anchoring dopamine release sites to dopamine-sensing targets.dopamine synapse | neuroligin-2 | medium spiny neuron | striatum C hemical synapses comprise presynaptic machinery for transmitter release and postsynaptic machinery for receptor-mediated signal transduction in a neurochemically matched manner. They are classified into Gray type-I and type-II synapses by asymmetric or symmetric membrane density, respectively, of the preand postsynaptic structures (1). Most, if not all, asymmetric and symmetric synapses are excitatory and inhibitory, respectively, as they selectively express ionotropic glutamate or GABA/glycine receptors together with their specific scaffolding proteins (2). Neurochemical matching of chemical synapses is controlled by activity-dependent mechanisms (3, 4), and mediated by transmembrane adhesion proteins and secreted molecules (5). The neuroligin (NL) family comprises postsynaptic adhesion molecules that form transsynaptic contacts with presynaptic neurexins (Nrxn) (6). Of note, NL1 and NL2 are selectively expressed at glutamatergic and GABAergic synapses, respectively (7,8), and are required for activity-dependent specification of the corresponding synapses (9).Midbrain dopamine neurons project densely to the striat...

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“…More broadly, regulation of TH expression by transcription, RNA stability, and translation is influenced by many factors [139–141]. In midbrain DA neurons, cAMP can induce translation of TH mRNA, increasing TH protein and activity without altering TH mRNA levels [142].…”

Section: Regulation Of Dopamine Releasementioning

confidence: 99%

“…In addition, post-translational modification plays a key role in the regulation of TH activity. TH phosphorylation, which involves many steps [141], influences the affinity of TH for its cofactor BH 4 and affects interactions of TH with other regulatory proteins, each of which could regulate quantal size.…”

Section: Regulation Of Dopamine Releasementioning

confidence: 99%

Striatal dopamine neurotransmission: Regulation of release and uptake

2016

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Dopamine (DA) transmission is governed by processes that regulate release from axonal boutons in the forebrain and the somatodendritic compartment in midbrain, and by clearance by the DA transporter, diffusion, and extracellular metabolism. We review how axonal DA release is regulated by neuronal activity and by autoreceptors and heteroreceptors, and address how quantal release events are regulated in size and frequency. In brain regions densely innervated by DA axons, DA clearance is due predominantly to uptake by the DA transporter, whereas in cortex, midbrain, and other regions with relatively sparse DA inputs, the norepinephrine transporter and diffusion are involved. We discuss the role of DA uptake in restricting the sphere of influence of DA and in temporal accumulation of extracellular DA levels upon successive action potentials. The tonic discharge activity of DA neurons may be translated into a tonic extracellular DA level, whereas their bursting activity can generate discrete extracellular DA transients.

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Mechanisms of dopamine quantal size regulation

Cited by 20 publications

References 226 publications

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Neuropsychiatric disease–associated genetic variants of the dopamine transporter display heterogeneous molecular phenotypes

Dopamine synapse is a neuroligin-2–mediated contact between dopaminergic presynaptic and GABAergic postsynaptic structures

Striatal dopamine neurotransmission: Regulation of release and uptake

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