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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 68545

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Prof. Dr. Marc Ekker

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Department of Biology, Faculty of Science, University of Ottawa, Ottawa, ON K1N 6N5, Canada
Interests: brain development and regeneration; development of dopamine and GABA neurons; control of gene expression; transgenic models; evolution of developmental mechanisms; zebrafish models of disease including Parkinson's disease
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Dear Colleagues,

The neurotransmitter dopamine plays crucial roles within the central nervous system, influencing multiple neural pathways and associated behaviors such as locomotion, reward mechanisms, neuroendocrine control, and emotion, to name but a few. Dysfunction of dopamine systems, including degeneration of dopamine neurons, are associated with numerous diseases. Some of the medications used to treat these diseases act by altering the effects of dopamine. This Special Issue on “Dopamine in Health and Disease” will present a selection of original research papers or reviews that address such topics as cellular mechanisms of disease affecting dopaminergic systems, genetic influences on dopamine neuron health and function, animal models of dopamine neurons loss and regeneration, and novel therapeutics for pathologies that involve dopamine neurons.

Prof. Dr. Marc Ekker
Guest Editor

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Keywords

dopamine
disease models
mitochondria
Parkinson’s disease
schizophrenia

Related Special Issue

Dopamine in Health and Disease 2.0 in Biomedicines (4 articles)

Published Papers (14 papers)

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Editorial

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3 pages, 159 KiB

Open AccessEditorial

Dopamine in Health and Disease

by Marc Ekker

Biomedicines 2021, 9(11), 1644; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111644 - 09 Nov 2021

Cited by 1 | Viewed by 1542

Abstract

The neurotransmitter dopamine (DA) is generally associated with Parkinson’s disease (PD) [...] Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

Research

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17 pages, 3096 KiB

Open AccessArticle

Dopamine Transporter Genetic Reduction Induces Morpho-Functional Changes in the Enteric Nervous System

by Silvia Cerantola, Valentina Caputi, Gabriella Contarini, Maddalena Mereu, Antonella Bertazzo, Annalisa Bosi, Davide Banfi, Dante Mantini, Cristina Giaroni and Maria Cecilia Giron

Biomedicines 2021, 9(5), 465; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9050465 - 24 Apr 2021

Cited by 11 | Viewed by 2490

Abstract

Antidopaminergic gastrointestinal prokinetics are indeed commonly used to treat gastrointestinal motility disorders, although the precise role of dopaminergic transmission in the gut is still unclear. Since dopamine transporter (DAT) is involved in several brain disorders by modulating extracellular dopamine in the central nervous system, this study evaluated the impact of DAT genetic reduction on the morpho-functional integrity of mouse small intestine enteric nervous system (ENS). In DAT heterozygous (DAT^+/−) and wild-type (DAT^+/+) mice (14 ± 2 weeks) alterations in small intestinal contractility were evaluated by isometrical assessment of neuromuscular responses to receptor and non-receptor-mediated stimuli. Changes in ENS integrity were studied by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (). DAT genetic reduction resulted in a significant increase in dopamine-mediated effects, primarily via D1 receptor activation, as well as in reduced cholinergic response, sustained by tachykininergic and glutamatergic neurotransmission via NMDA receptors. These functional anomalies were associated to architectural changes in the neurochemical coding and S100β immunoreactivity in small intestine myenteric plexus. Our study provides evidence that genetic-driven DAT defective activity determines anomalies in ENS architecture and neurochemical coding together with ileal dysmotility, highlighting the involvement of dopaminergic system in gut disorders, often associated to neurological conditions. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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14 pages, 4551 KiB

Open AccessArticle

Tcf4 Is Involved in Subset Specification of Mesodiencephalic Dopaminergic Neurons

by Simone Mesman, Iris Wever and Marten P. Smidt

Biomedicines 2021, 9(3), 317; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9030317 - 20 Mar 2021

Cited by 6 | Viewed by 2266

Abstract

During development, mesodiencephalic dopaminergic (mdDA) neurons form into different molecular subsets. Knowledge of which factors contribute to the specification of these subsets is currently insufficient. In this study, we examined the role of Tcf4, a member of the E-box protein family, in mdDA neuronal development and subset specification. We show that Tcf4 is expressed throughout development, but is no longer detected in adult midbrain. Deletion of Tcf4 results in an initial increase in TH-expressing neurons at E11.5, but this normalizes at later embryonic stages. However, the caudal subset marker Nxph3 and rostral subset marker Ahd2 are affected at E14.5, indicating that Tcf4 is involved in correct differentiation of mdDA neuronal subsets. At P0, expression of these markers partially recovers, whereas expression of Th transcript and TH protein appears to be affected in lateral parts of the mdDA neuronal population. The initial increase in TH-expressing cells and delay in subset specification could be due to the increase in expression of the bHLH factor Ascl1, known for its role in mdDA neuronal differentiation, upon loss of Tcf4. Taken together, our data identified a minor role for Tcf4 in mdDA neuronal development and subset specification. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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14 pages, 3089 KiB

Open AccessArticle

Loss of parla Function Results in Inactivity, Olfactory Impairment, and Dopamine Neuron Loss in Zebrafish

by Rawan Merhi, Michael Kalyn, Amanda Zhu-Pawlowsky and Marc Ekker

Biomedicines 2021, 9(2), 205; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020205 - 18 Feb 2021

Cited by 10 | Viewed by 3568

Abstract

The presenilin-associated rhomboid-like (PARL) gene was found to contribute to mitochondrial morphology and function and was linked to familial Parkinson’s disease (PD). The PARL gene product is a mitochondrial intramembrane cleaving protease that acts on a number of mitochondrial proteins involved in mitochondrial morphology, apoptosis, and mitophagy. To date, functional and genetic studies of PARL have been mainly performed in mammals. However, little is known about PARL function and its role in dopaminergic (DA) neuron development in vertebrates. The zebrafish genome comprises two PARL paralogs: parla and parlb. Here, we established a loss-of-function mutation in parla via CRISPR/Cas9-mediated mutagenesis. We examined DA neuron numbers in the adult brain and expression of genes associated with DA neuron function in larvae and adults. We show that loss of parla function results in loss of DA neurons, mainly in the olfactory bulb. Changes in the levels of tyrosine hydroxylase transcripts supported this neuronal loss. Expression of fis1, a gene involved in mitochondrial fission, was increased in parla mutants. Finally, we showed that loss of parla function translates into impaired olfaction and altered locomotion parameters. These results suggest a role for parla in the development and/or maintenance of DA neuron function in zebrafish. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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16 pages, 3016 KiB

Open AccessArticle

Early Adolescence Prefrontal Cortex Alterations in Female Rats Lacking Dopamine Transporter

by Placido Illiano, Damiana Leo, Raul R. Gainetdinov and Marta Pardo

Biomedicines 2021, 9(2), 157; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020157 - 05 Feb 2021

Cited by 10 | Viewed by 2398

Abstract

Monoamine dysfunctions in the prefrontal cortex (PFC) can contribute to diverse neuropsychiatric disorders, including ADHD, bipolar disorder, PTSD and depression. Disrupted dopamine (DA) homeostasis, and more specifically dopamine transporter (DAT) alterations, have been reported in a variety of psychiatric and neurodegenerative disorders. Recent studies using female adult rats heterozygous (DAT+/−) and homozygous (DAT−/−) for DAT gene, showed the utility of those rats in the study of PTSD and ADHD. Currently, a gap in the knowledge of these disorders affecting adolescent females still represents a major limit for the development of appropriate treatments. The present work focuses on the characterization of the PFC function under conditions of heterozygous and homozygous ablation of DAT during early adolescence based on the known implication of DAT and PFC DA in psychopathology during adolescence. We report herein that genetic ablation of DAT in the early adolescent PFC of female rats leads to changes in neuronal and glial cell homeostasis. In brief, we observed a concurrent hyperactive phenotype, accompanied by PFC alterations in glutamatergic neurotransmission, signs of neurodegeneration and glial activation in DAT-ablated rats. The present study provides further understanding of underlying neuroinflammatory pathological processes that occur in DAT-ablated female rats, what can provide novel investigational approaches in human diseases. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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14 pages, 7183 KiB

Open AccessEditor’s ChoiceArticle

Dopamine D2 Long Receptors Are Critical for Caveolae-Mediated α-Synuclein Uptake in Cultured Dopaminergic Neurons

by Ichiro Kawahata, Tomoki Sekimori, Haoyang Wang, Yanyan Wang, Toshikuni Sasaoka, Luc Bousset, Ronald Melki, Tomohiro Mizobata, Yasushi Kawata and Kohji Fukunaga

Biomedicines 2021, 9(1), 49; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9010049 - 08 Jan 2021

Cited by 23 | Viewed by 3409

Abstract

α-synuclein accumulation into dopaminergic neurons is a pathological hallmark of Parkinson’s disease. We previously demonstrated that fatty acid-binding protein 3 (FABP3) is critical for α-synuclein uptake and propagation to accumulate in dopaminergic neurons. FABP3 is abundant in dopaminergic neurons and interacts with dopamine D2 receptors, specifically the long type (D_2L). Here, we investigated the importance of dopamine D_2L receptors in the uptake of α-synuclein monomers and their fibrils. We employed mesencephalic neurons derived from dopamine D_2L^−/−, dopamine D2 receptor null (D2 null), FABP3^−/−, and wild type C57BL6 mice, and analyzed the uptake ability of fluorescence-conjugated α-synuclein monomers and fibrils. We found that D_2L receptors are co-localized with FABP3. Immunocytochemistry revealed that TH⁺ D2L^−/− or D2 null neurons do not take up α-synuclein monomers. The deletion of α-synuclein C-terminus completely abolished the uptake to dopamine neurons. Likewise, dynasore, a dynamin inhibitor, and caveolin-1 knockdown also abolished the uptake. D_2L and FABP3 were also critical for α-synuclein fibrils uptake. D_2L and accumulated α-synuclein fibrils were well co-localized. These data indicate that dopamine D_2L with a caveola structure coupled with FABP3 is critical for α-synuclein uptake by dopaminergic neurons, suggesting a novel pathogenic mechanism of synucleinopathies, including Parkinson’s disease. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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Review

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29 pages, 1417 KiB

Open AccessReview

Integrating the Roles of Midbrain Dopamine Circuits in Behavior and Neuropsychiatric Disease

by Allen PF Chen, Lu Chen, Thomas A. Kim and Qiaojie Xiong

Biomedicines 2021, 9(6), 647; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9060647 - 07 Jun 2021

Cited by 20 | Viewed by 7309

Abstract

Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson’s, Schizophrenia, addiction, and Alzheimer’s disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA’s behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia’s dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA’s reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson’s disease, addiction, and Alzheimer’s Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA’s necessity and contribution to the functional plasticity of different striatal regions. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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17 pages, 877 KiB

Open AccessReview

The Potential Role of Dopamine in Mediating Motor Function and Interpersonal Synchrony

by Hila Z. Gvirts Probolovski and Anat Dahan

Biomedicines 2021, 9(4), 382; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040382 - 05 Apr 2021

Cited by 7 | Viewed by 3599

Abstract

Motor functions in general and motor planning in particular are crucial for our ability to synchronize our movements with those of others. To date, these co-occurring functions have been studied separately, and as yet it is unclear whether they share a common biological mechanism. Here, we synthesize disparate recent findings on motor functioning and interpersonal synchrony and propose that these two functions share a common neurobiological mechanism and adhere to the same principles of predictive coding. Critically, we describe the pivotal role of the dopaminergic system in modulating these two distinct functions. We present attention deficit hyperactivity disorder (ADHD) as an example of a disorder that involves the dopaminergic system and describe deficits in motor and interpersonal synchrony. Finally, we suggest possible directions for future studies emphasizing the role of dopamine modulation as a link between social and motor functioning. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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21 pages, 7131 KiB

Open AccessReview

Single-Cell RNA Sequencing in Parkinson’s Disease

by Shi-Xun Ma and Su Bin Lim

Biomedicines 2021, 9(4), 368; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040368 - 01 Apr 2021

Cited by 14 | Viewed by 7710

Abstract

Single-cell and single-nucleus RNA sequencing (sc/snRNA-seq) technologies have enhanced the understanding of the molecular pathogenesis of neurodegenerative disorders, including Parkinson’s disease (PD). Nonetheless, their application in PD has been limited due mainly to the technical challenges resulting from the scarcity of postmortem brain tissue and low quality associated with RNA degradation. Despite such challenges, recent advances in animals and human in vitro models that recapitulate features of PD along with sequencing assays have fueled studies aiming to obtain an unbiased and global view of cellular composition and phenotype of PD at the single-cell resolution. Here, we reviewed recent sc/snRNA-seq efforts that have successfully characterized diverse cell-type populations and identified cell type-specific disease associations in PD. We also examined how these studies have employed computational and analytical tools to analyze and interpret the rich information derived from sc/snRNA-seq. Finally, we highlighted important limitations and emerging technologies for addressing key technical challenges currently limiting the integration of new findings into clinical practice. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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23 pages, 2027 KiB

Open AccessReview

The Role of the Renal Dopaminergic System and Oxidative Stress in the Pathogenesis of Hypertension

by Waleed N. Qaddumi and Pedro A. Jose

Biomedicines 2021, 9(2), 139; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020139 - 01 Feb 2021

Cited by 16 | Viewed by 8370

Abstract

The kidney is critical in the long-term regulation of blood pressure. Oxidative stress is one of the many factors that is accountable for the development of hypertension. The five dopamine receptor subtypes (D₁R–D₅R) have important roles in the regulation of blood pressure through several mechanisms, such as inhibition of oxidative stress. Dopamine receptors, including those expressed in the kidney, reduce oxidative stress by inhibiting the expression or action of receptors that increase oxidative stress. In addition, dopamine receptors stimulate the expression or action of receptors that decrease oxidative stress. This article examines the importance and relationship between the renal dopaminergic system and oxidative stress in the regulation of renal sodium handling and blood pressure. It discusses the current information on renal dopamine receptor-mediated antioxidative network, which includes the production of reactive oxygen species and abnormalities of renal dopamine receptors. Recognizing the mechanisms by which renal dopamine receptors regulate oxidative stress and their degree of influence on the pathogenesis of hypertension would further advance the understanding of the pathophysiology of hypertension. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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13 pages, 1574 KiB

Open AccessReview

Dopamine in Health and Disease: Much More Than a Neurotransmitter

by Rafael Franco, Irene Reyes-Resina and Gemma Navarro

Biomedicines 2021, 9(2), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020109 - 22 Jan 2021

Cited by 76 | Viewed by 11861

Abstract

Dopamine is derived from an amino acid, phenylalanine, which must be obtained through the diet. Dopamine, known primarily to be a neurotransmitter involved in almost any higher executive action, acts through five types of G-protein-coupled receptors. Dopamine has been studied extensively for its neuronal handling, synaptic actions, and in relation to Parkinson’s disease. However, dopamine receptors can be found extra-synaptically and, in addition, they are not only expressed in neurons, but in many types of mammalian cells, inside and outside the central nervous system (CNS). Recent studies show a dopamine link between the gut and the CNS; the mechanisms are unknown, but they probably require cells to act as mediators and the involvement of the immune system. In fact, dopamine receptors are expressed in almost any cell of the immune system where dopamine regulates various processes, such as antigen presentation, T-cell activation, and inflammation. This likely immune cell-mediated linkage opens up a new perspective for the use of dopamine-related drugs, i.e., agonist–antagonist–allosteric modulators of dopamine receptors, in a variety of diseases. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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15 pages, 1125 KiB

Open AccessReview

¹¹C- and ¹⁸F-Radiotracers for In Vivo Imaging of the Dopamine System: Past, Present and Future

by Michael R. Kilbourn

Biomedicines 2021, 9(2), 108; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9020108 - 22 Jan 2021

Cited by 11 | Viewed by 3129

Abstract

The applications of positron emission tomography (PET) imaging to study brain biochemistry, and in particular the aspects of dopamine neurotransmission, have grown significantly over the 40 years since the first successful in vivo imaging studies in humans. In vivo PET imaging of dopaminergic functions of the central nervous system (CNS) including dopamine synthesis, vesicular storage, synaptic release and receptor binding, and reuptake processes, are now routinely used for studies in neurology, psychiatry, drug abuse and addiction, and drug development. Underlying these advances in PET imaging has been the development of the unique radiotracers labeled with positron-emitting radionuclides such as carbon-11 and fluorine-18. This review focuses on a selection of the more accepted and utilized PET radiotracers currently available, with a look at their past, present and future. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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19 pages, 1152 KiB

Open AccessReview

Two Players in the Field: Hierarchical Model of Interaction between the Dopamine and Acetylcholine Signaling Systems in the Striatum

by Jaromir Myslivecek

Biomedicines 2021, 9(1), 25; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9010025 - 01 Jan 2021

Cited by 12 | Viewed by 3714

Abstract

Tight interactions exist between dopamine and acetylcholine signaling in the striatum. Dopaminergic neurons express muscarinic and nicotinic receptors, and cholinergic interneurons express dopamine receptors. All neurons in the striatum are pacemakers. An increase in dopamine release is activated by stopping acetylcholine release. The coordinated timing or synchrony of the direct and indirect pathways is critical for refined movements. Changes in neurotransmitter ratios are considered a prominent factor in Parkinson’s disease. In general, drugs increase striatal dopamine release, and others can potentiate both dopamine and acetylcholine release. Both neurotransmitters and their receptors show diurnal variations. Recently, it was observed that reward function is modulated by the circadian system, and behavioral changes (hyperactivity and hypoactivity during the light and dark phases, respectively) are present in an animal model of Parkinson’s disease. The striatum is one of the key structures responsible for increased locomotion in the active (dark) period in mice lacking M₄ muscarinic receptors. Thus, we propose here a hierarchical model of the interaction between dopamine and acetylcholine signaling systems in the striatum. The basis of this model is their functional morphology. The next highest mode of interaction between these two neurotransmitter systems is their interaction at the neurotransmitter/receptor/signaling level. Furthermore, these interactions contribute to locomotor activity regulation and reward behavior, and the topmost level of interaction represents their biological rhythmicity. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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26 pages, 1770 KiB

Open AccessReview

The Links between Parkinson’s Disease and Cancer

by Maria Ejma, Natalia Madetko, Anna Brzecka, Konstanty Guranski, Piotr Alster, Marta Misiuk-Hojło, Siva G. Somasundaram, Cecil E. Kirkland and Gjumrakch Aliev

Biomedicines 2020, 8(10), 416; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8100416 - 14 Oct 2020

Cited by 38 | Viewed by 5106

Abstract

Epidemiologic studies indicate a decreased incidence of most cancer types in Parkinson’s disease (PD) patients. However, some neoplasms are associated with a higher risk of occurrence in PD patients. Both pathologies share some common biological pathways. Although the etiologies of PD and cancer are multifactorial, some factors associated with PD, such as α-synuclein aggregation; mutations of PINK1, PARKIN, and DJ-1; mitochondrial dysfunction; and oxidative stress can also be involved in cancer proliferation or cancer suppression. The main protein associated with PD, i.e., α-synuclein, can be involved in some types of neoplastic formations. On the other hand, however, its downregulation has been found in the other cancers. PINK1 can act as oncogenic or a tumor suppressor. PARKIN dysfunction may lead to some cancers’ growth, and its expression may be associated with some tumors’ suppression. DJ-1 mutation is involved in PD pathogenesis, but its increased expression was found in some neoplasms, such as melanoma or breast, lung, colorectal, uterine, hepatocellular, and nasopharyngeal cancers. Both mitochondrial dysfunction and oxidative stress are involved in PD and cancer development. The aim of this review is to summarize the possible associations between PD and carcinogenesis. Full article

(This article belongs to the Special Issue Dopamine in Health and Disease)

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