scholarly journals GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Bradley M. Roberts ◽  
Natalie M. Doig ◽  
Katherine R. Brimblecombe ◽  
Emanuel F. Lopes ◽  
Ruth E. Siddorn ◽  
...  
Keyword(s):  
Dorsal Striatum ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
Nucleus Accumbens Core ◽  
Dorsolateral Striatum ◽  
Striatal Projection Neurons ◽  
Maladaptive Plasticity ◽  
Uptake Transporters ◽  
Da Release ◽  
Accumbens Core

Abstract Striatal dopamine (DA) is critical for action and learning. Recent data show that DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be determined by plasma membrane GABA uptake transporters (GATs) located on astrocytes and neurons. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs are downregulated, tonic GABAergic inhibition of DA release augmented, and nigrostriatal GABA co-release attenuated. These data define previously unappreciated and important roles for GATs and astrocytes in supporting DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.

scholarly journals Astrocytic striatal GABA transporter activity governs dopamine release and shows maladaptive downregulation in early parkinsonism

2019 ◽  
Author(s):  
Bradley M. Roberts ◽  
Natalie M. Doig ◽  
Katherine R. Brimblecombe ◽  
Emanuel F. Lopes ◽  
Ruth E. Siddorn ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tonic Inhibition ◽  
Gaba Uptake ◽  
Projection Neurons ◽  
List Type ◽  
Dorsolateral Striatum ◽  
Gaba Transporters ◽  
Gaba Inhibition ◽  
Da Release ◽  
Accumbens Core

SummaryStriatal dopamine (DA) is critical for action and learning. Recent data show DA release is under tonic inhibition by striatal GABA. Ambient striatal GABA tone on striatal projection neurons can be governed by plasma membrane GABA uptake transporters (GATs) on astrocytes. However, whether striatal GATs and astrocytes determine DA output are unknown. We reveal that DA release in mouse dorsolateral striatum, but not nucleus accumbens core, is governed by GAT-1 and GAT-3. These GATs are partly localized to astrocytes, and are enriched in dorsolateral striatum compared to accumbens core. In a mouse model of early parkinsonism, GATs were downregulated and tonic GABAergic inhibition of DA release augmented, with corresponding attenuation of GABA co-release from dopaminergic axons. These data define previously unappreciated and important roles for GATs and astrocytes in determining DA release in striatum, and reveal a maladaptive plasticity in early parkinsonism that impairs DA output in vulnerable striatal regions.HighlightsGABA transporters set the level of GABA inhibition of DA output in dorsal striatumAstrocytes facilitate DA release levels by limiting tonic GABA inhibitionTonic inhibition of DA release is augmented in a mouse model of early parkinsonismDA and GABA co-release are reduced in a mouse model of early parkinsonism

scholarly journals Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 709
Author(s):  
Bradley M. Roberts ◽  
Emanuel F. Lopes ◽  
Stephanie J. Cragg
Keyword(s):  
Gabab Receptors ◽  
Striatal Dopamine ◽  
Aminobutyric Acid ◽  
Gaba Uptake ◽  
Short Term Plasticity ◽  
Psychomotor Disorders ◽  
Gabaa And Gabab Receptors ◽  
Uptake Transporters ◽  
Gabaergic Modulation ◽  
Da Release

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

scholarly journals Repression of Dlx1/2 Signaling by Nolz-1/Znf503 is Essential for Parcellation of the Striatal Complex into Dorsal and Ventral Striatum

2018 ◽  
Author(s):  
Kuan-Ming Lu ◽  
Shih-Yun Chen ◽  
Hsin-An Ko ◽  
Ting-Hao Huang ◽  
Janice Hsin-Jou Hao ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Ventral Striatum ◽  
Dorsal Striatum ◽  
Clinical Importance ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Addictive Disorders ◽  
Striatal Projection Neurons ◽  
Cells Of Origin ◽  
Set Up

ABSTRACTThe division of the striatum into dorsal and ventral districts is of central clinical importance. The dorsal striatum is differentially affected in Huntington’s disease, dopamine in the ventral striatum is differentially spared in Parkinson’s disease, and human brain imaging studies implicate the ventral striatum in addictive disorders. If fits that the dorsal striatum contains the cells of origin of the direct and indirect basal ganglia pathways for motor control. The ventral striatum is a node in neural circuits related to motivation and affect. Despite these striking neurobiologic contrasts, there is almost no information about how the dorsal and ventral divisions of the striatum are set up during development. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of developing striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and ventral striatum including the cell origin of the direct and indirect pathways. We show that Nolz-1 suppresses Dlx1/2 expression. Deletion of Nolz-1 or over-expression of Dlx1/2 can produce a striatal phenotype characterized by withered dorsal striatum and a swollen ventral striatum, and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. This evidence suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into the developing striatum.

scholarly journals Dopamine D4 Receptor Is a Regulator of Morphine-Induced Plasticity in the Rat Dorsal Striatum

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 31
Author(s):  
Alicia Rivera ◽  
Diana Suárez-Boomgaard ◽  
Cristina Miguelez ◽  
Alejandra Valderrama-Carvajal ◽  
Jérôme Baufreton ◽  
...  
Keyword(s):  
Critical Role ◽  
Combined Treatment ◽  
Dorsal Striatum ◽  
Prolonged Treatment ◽  
Projection Neurons ◽  
Spine Density ◽  
Dopamine D4 Receptor ◽  
Striatal Projection Neurons ◽  
D4 Receptor

Long-term exposition to morphine elicits structural and synaptic plasticity in reward-related regions of the brain, playing a critical role in addiction. However, morphine-induced neuroadaptations in the dorsal striatum have been poorly studied despite its key function in drug-related habit learning. Here, we show that prolonged treatment with morphine triggered the retraction of the dendritic arbor and the loss of dendritic spines in the dorsal striatal projection neurons (MSNs). In an attempt to extend previous findings, we also explored whether the dopamine D4 receptor (D4R) could modulate striatal morphine-induced plasticity. The combined treatment of morphine with the D4R agonist PD168,077 produced an expansion of the MSNs dendritic arbors and restored dendritic spine density. At the electrophysiological level, PD168,077 in combination with morphine altered the electrical properties of the MSNs and decreased their excitability. Finally, results from the sustantia nigra showed that PD168,077 counteracted morphine-induced upregulation of μ opioid receptors (MOR) in striatonigral projections and downregulation of G protein-gated inward rectifier K+ channels (GIRK1 and GIRK2) in dopaminergic cells. The present results highlight the key function of D4R modulating morphine-induced plasticity in the dorsal striatum. Thus, D4R could represent a valuable pharmacological target for the safety use of morphine in pain management.

scholarly journals MMP-1 overexpression selectively alters inhibition in D1 spiny projection neurons in the mouse nucleus accumbens core

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Nour Al-muhtasib ◽  
Patrick A. Forcelli ◽  
Katherine E. Conant ◽  
Stefano Vicini
Keyword(s):  
Nucleus Accumbens ◽  
Projection Neurons ◽  
Nucleus Accumbens Core ◽  
Accumbens Core

scholarly journals Parcellation of the striatal complex into dorsal and ventral districts

2020 ◽  
Vol 117 (13) ◽  
pp. 7418-7429 ◽  
Author(s):  
Shih-Yun Chen ◽  
Kuan-Ming Lu ◽  
Hsin-An Ko ◽  
Ting-Hao Huang ◽  
Janice Hsin-Jou Hao ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Ventral Striatum ◽  
Dorsal Striatum ◽  
Clinical Importance ◽  
Projection Neurons ◽  
Striatal Neurons ◽  
Striatal Projection Neurons ◽  
Tier System ◽  
And Migration ◽  
Set Up

The striatal complex of basal ganglia comprises two functionally distinct districts. The dorsal district controls motor and cognitive functions. The ventral district regulates the limbic function of motivation, reward, and emotion. The dorsoventral parcellation of the striatum also is of clinical importance as differential striatal pathophysiologies occur in Huntington’s disease, Parkinson’s disease, and drug addiction disorders. Despite these striking neurobiologic contrasts, it is largely unknown how the dorsal and ventral divisions of the striatum are set up. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and the ventral striata including the D1-direct and D2-indirect pathways. We show that Nolz-1, through the I12b enhancer, represses Dlx1/2, allowing normal migration of striatal neurons to dorsal and ventral locations. We demonstrate that deletion, up-regulation, and down-regulation of Nolz-1 and Dlx1/2 can produce a striatal phenotype characterized by a withered dorsal striatum and an enlarged ventral striatum and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. Our study indicates that the two-tier system of striatal complex is built by coupling of cell-type identity and migration and suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into developing striata.

scholarly journals Habit formation coincides with shifts in reinforcement representations in the sensorimotor striatum

2016 ◽  
Vol 115 (3) ◽  
pp. 1487-1498 ◽  
Author(s):  
Kyle S. Smith ◽  
Ann M. Graybiel
Keyword(s):  
Dorsal Striatum ◽  
Early Response ◽  
Outcome Evaluation ◽  
Projection Neurons ◽  
Maze Task ◽  
Central Function ◽  
Dorsolateral Striatum ◽  
Compulsive Behaviors ◽  
Selective Sensitivity ◽  
Goal Value

Evaluating outcomes of behavior is a central function of the striatum. In circuits engaging the dorsomedial striatum, sensitivity to goal value is accentuated during learning, whereas outcome sensitivity is thought to be minimal in the dorsolateral striatum and its habit-related corticostriatal circuits. However, a distinct population of projection neurons in the dorsolateral striatum exhibits selective sensitivity to rewards. Here, we evaluated the outcome-related signaling in such neurons as rats performed an instructional T-maze task for two rewards. As the rats formed maze-running habits and then changed behavior after reward devaluation, we detected outcome-related spike activity in 116 units out of 1,479 recorded units. During initial training, nearly equal numbers of these units fired preferentially either after rewarded runs or after unrewarded runs, and the majority were responsive at only one of two reward locations. With overtraining, as habits formed, firing in nonrewarded trials almost disappeared, and reward-specific firing declined. Thus error-related signaling was lost, and reward signaling became generalized. Following reward devaluation, in an extinction test, postgoal activity was nearly undetectable, despite accurate running. Strikingly, when rewards were then returned, postgoal activity reappeared and recapitulated the original early response pattern, with nearly equal numbers responding to rewarded and unrewarded runs and to single rewards. These findings demonstrate that outcome evaluation in the dorsolateral striatum is highly plastic and tracks stages of behavioral exploration and exploitation. These signals could be a new target for understanding compulsive behaviors that involve changes to dorsal striatum function.

scholarly journals D1 and D2 systems converge in the striatum to update goal-directed learning

2019 ◽  
Author(s):  
Miriam Matamales ◽  
Alice E. McGovern ◽  
Jia Dai Mi ◽  
Stuart B. Mazzone ◽  
Bernard W. Balleine ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Behavioral Control ◽  
Dorsal Striatum ◽  
Projection Neurons ◽  
Extinction Learning ◽  
Striatal Projection Neurons ◽  
New Learning ◽  
Large Ensembles ◽  
Directed Learning

AbstractExtinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits mediating goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of striatal projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN trans-modulation across the dorsal striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.

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