Dopamine D1–D2 Receptor Heteromer in Dual Phenotype GABA/Glutamate-Coexpressing Striatal Medium Spiny Neurons: Regulation of BDNF, GAD67 and VGLUT1/2

Abstract D2 receptor blockade has been cited as a principal mechanism of action of all antipsychotic medications, but is poorly predictive of symptom improvement or neurophysiological responses recorded using human brain imaging. A potential hurdle in interpreting such human imaging studies arises from the inability to distinguish activity within neuronal subcircuits. We used single cell resolution imaging to record activity in distinct populations of medium spiny neurons in vivo within the mouse ventral striatum, a structure associated with schizophrenia symptoms and antipsychotic therapeutic efficacy. While we expected the antipsychotic haloperidol to excite D2 receptor expressing neurons, we report a strong cellular depression mediated by the hypofunctional NMDA channel, which may be mediated in part by the action of haloperidol on the sigma1 receptor. Altogether, the impact of haloperidol on Ca2+ events in D2 receptor expressing neurons predicted psychomotor inhibition. Our results elucidate mechanisms by which antipsychotics act rapidly in the brain to impact psychomotor outputs.

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Mechanisms of dopamine-mediated incentive learning

10.1093/oso/9780198824091.003.0012 ◽

2018 ◽

Author(s):

Richard J. Beninger

Keyword(s):

Dendritic Spines ◽

D2 Receptor ◽

D1 Receptor ◽

Medium Spiny Neurons ◽

Prediction Errors ◽

Incentive Learning ◽

Spiny Neurons ◽

Negative Prediction ◽

Response Systems ◽

Subsequent Wave

Mechanisms of dopamine-mediated incentive learning explains how sensory events, resulting from an animal’s movement and the environment, activate cortical glutamatergic projections to dendritic spines of striatal medium spiny neurons to initiate a wave of phosphorylation. If no rewarding stimulus is encountered, a subsequent wave of phosphatase activity undoes the phosphorylation. If a rewarding stimulus is encountered, dopamine initiates a cascade of events in D1 receptor-expressing medium spiny neurons that may prevent the phosphatase effects and work synergistically with signaling events produced by glutamate. As a result, corticostriatal synapses have a greater impact on response systems; this may be part of the mechanism of incentive learning. Dopamine acting on dendritic spines of D2 receptor-expressing medium spiny neurons may prevent synaptic strengthening by inhibiting adenosine signaling; these synapses may be weakened through mechanisms involving endocannabinoids. When dopamine concentrations drop, e.g. during negative prediction errors, the opposite may occur, producing inverse incentive learning.

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Restoration of KCC2 Membrane Localization in Striatal Dopamine D2 Receptor-Expressing Medium Spiny Neurons Rescues Locomotor Deficits in HIV Tat-Transgenic Mice

ASN NEURO ◽

10.1177/17590914211022089 ◽

2021 ◽

Vol 13 ◽

pp. 175909142110220

Author(s):

Aaron J. Barbour ◽

Sara R. Nass ◽

Yun K. Hahn ◽

Kurt F. Hauser ◽

Pamela E. Knapp

Keyword(s):

Transgenic Mice ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Brain Regions ◽

D1 Receptor ◽

Membrane Localization ◽

Hippocampal Damage ◽

Medium Spiny Neurons ◽

Dopamine D2 ◽

Spiny Neurons

People infected with HIV (PWH) are highly susceptible to striatal and hippocampal damage. Motor and memory impairments are common among these patients, likely as behavioral manifestations of damage to these brain regions. GABAergic dysfunction from HIV infection and viral proteins such as transactivator of transcription (Tat) have been well documented. We recently demonstrated that the neuron specific Cl− extruder, K+ Cl− cotransporter 2 (KCC2), is diminished after exposure to HIV proteins, including Tat, resulting in disrupted GABAAR-mediated hyperpolarization and inhibition. Here, we utilized doxycycline (DOX)-inducible, GFAP-driven HIV-1 Tat transgenic mice to further explore this phenomenon. After two weeks of Tat expression, we found no changes in hippocampal KCC2 levels, but a significant decrease in the striatum that was associated with hyperlocomotion in the open field assay. We were able to restore KCC2 activity and baseline locomotion with the KCC2 enhancer, CLP290. Additionally, we found that CLP290, whose mechanism of action has yet to be described, acts to restore phosphorylation of serine 940 resulting in increased KCC2 membrane localization. We also examined neuronal subpopulation contributions to the noted effects and found significant differences. Dopamine D2 receptor-expressing medium spiny neurons (MSNs) were selectively vulnerable to Tat-induced KCC2 loss, with no changes observed in dopamine D1 receptor-expressing MSNs. These results suggest that disinhibition/diminished hyperpolarization of dopamine D2 receptor-expressing MSNs can manifest as increased locomotion in this context. They further suggest that KCC2 activity might be a therapeutic target to alleviate motor disturbances related to HIV.

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S36. DIFFERENTIAL ENCODING OF SENSITIZATION AND CROSS SENSITIZATION TO PSYCHOSTIMULANTS AND ANTIPSYCHOTICS IN NUCLEUS ACCUMBENS D1- AND D2- RECEPTOR EXPRESSING MEDIUM SPINY NEURONS

Schizophrenia Bulletin ◽

10.1093/schbul/sby018.823 ◽

2018 ◽

Vol 44 (suppl_1) ◽

pp. S337-S338

Author(s):

Davide Amato ◽

Jasper Heinsbroek ◽

Peter W Kalivas

Keyword(s):

Nucleus Accumbens ◽

D2 Receptor ◽

Medium Spiny Neurons ◽

Differential Encoding ◽

Spiny Neurons

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Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia

Experimental Neurology ◽

10.1016/j.expneurol.2016.09.009 ◽

2016 ◽

Vol 286 ◽

pp. 32-39 ◽

Cited By ~ 18

Author(s):

Tanuja Bordia ◽

Danhui Zhang ◽

Xiomara A. Perez ◽

Maryka Quik

Keyword(s):

Tardive Dyskinesia ◽

D2 Receptor ◽

Medium Spiny Neurons ◽

Cholinergic Interneurons ◽

Spiny Neurons

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Accumbens D2-MSN hyperactivity drives behavioral supersensitivity

10.1101/2020.11.12.380667 ◽

2020 ◽

Author(s):

Anna Kruyer ◽

Jeffrey Parilla-Carerro ◽

Courtney Powell ◽

Lasse Brandt ◽

Stefan Gutwinski ◽

...

Keyword(s):

D2 Receptor ◽

Treatment Resistance ◽

Term Treatment ◽

Antipsychotic Treatment ◽

Medium Spiny Neurons ◽

Therapeutic Approaches ◽

Spiny Neurons ◽

Long Term Treatment ◽

Underlying Mechanisms

ABSTRACTAntipsychotic-induced behavioral supersensitivity is a problematic consequence of long-term treatment with antipsychotic drugs and is characterized by emergence of refractory symptoms and dyskinesias. The underlying mechanisms are unknown, and no rational approaches exist to prevent or reverse antipsychotic-induced supersensitivity. Here we describe major adaptations impacting populations of striatal medium spiny neurons (MSNs) during the development of behavioral supersensitivity and reveal a prominent role played by D2 receptor expressing MSNs. We show that enhanced D2-MSN activity underlies several symptoms spanning from psychostimulant sensitization, to antipsychotic treatment resistance and drug addiction. Our data warn against severe adverse events following antipsychotic treatment discontinuation and offer insight that may inform therapeutic approaches to overcome antipsychotic-induced supersensitivity.

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