The Dopamine D1–D2 Receptor Heteromer in Striatal Medium Spiny Neurons: Evidence for a Third Distinct Neuronal Pathway in Basal Ganglia

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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Striatal circuits support broadly opponent aspects of action suppression and production

10.1101/2020.06.30.180539 ◽

2020 ◽

Author(s):

Bruno F. Cruz ◽

Sofia Soares ◽

Joseph J. Paton

Keyword(s):

Basal Ganglia ◽

Behavioral Control ◽

Relative Activity ◽

The Body ◽

Medium Spiny Neurons ◽

Dorsolateral Striatum ◽

Spiny Neurons ◽

Over Time

SummaryImbalance between action suppression and production characterizes several basal ganglia (BG) disorders. Relatedly, the direct and indirect pathways of the BG are hypothesized to promote and suppress actions, respectively. Yet striatal direct (dMSNs) and indirect (iMSNs) medium spiny neurons are coactive around movement, apparently contradicting direct-indirect functional opponency. In the dorsolateral striatum of mice, we observed coactivation around movements, but elevated and diminished activity of iMSNs and dMSNs, respectively, during action suppression. Furthermore, relative activity of the two hemispheres evolved in opposite directions in the two pathways as the need to suppress movements to either side of the body developed over time. Lastly, optogenetic inhibition experiments revealed the necessity of iMSNs but not dMSNs for the proactive suppression of specific actions, and dMSNs but not iMSNs for generalized action vigor. These data demonstrate distinct yet still broadly opponent roles for the direct and indirect pathways in behavioral control.

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Direct and Indirect Pathway Neurons in Ventrolateral Striatum Differentially Regulate Licking Movement and Nigral Responses

10.1101/2021.04.11.439386 ◽

2021 ◽

Author(s):

Zhaorong Chen ◽

Zhi-Yu Zhang ◽

Taorong Xie ◽

Wen Zhang ◽

Yaping Li ◽

...

Keyword(s):

Basal Ganglia ◽

Rate Increase ◽

Drinking Behavior ◽

Medium Spiny Neurons ◽

Indirect Pathway ◽

Related Activity ◽

Tongue Protrusion ◽

D1 And D2 Receptors ◽

Spiny Neurons ◽

Output Neurons

SUMMARYDrinking behavior in rodents is characterized by stereotyped, rhythmic licking movement, which is regulated by the basal ganglia. It is unclear how direct and indirect pathways control the lick bout and individual lick event. We find that inactivating D1 and D2 receptors-expressing medium spiny neurons (MSNs) in the ventrolateral striatum (VLS) oppositely alters the number of licks in a bout. D1- and D2-MSNs exhibit similar patterns of lick sequence-related activity but different phases of oscillation time-locked to the lick cycle. On timescale of a lick cycle, transient inactivation of D1-MSNs during tongue protrusion reduces lick probability, whereas transient inactivation of D2-MSNs has no effect. On timescale of a lick bout, inactivation of D1-MSNs (D2-MSNs) causes rate increase (decrease) in a subset of basal ganglia output neurons that decrease firing during licking. Our results reveal the distinct roles of D1- and D2-MSNs in regulating licking at both coarse and fine timescales.

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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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Faculty Opinions recommendation of Phenotype of striatofugal medium spiny neurons in parkinsonian and dyskinetic nonhuman primates: a call for a reappraisal of the functional organization of the basal ganglia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1046604.496596 ◽

2006 ◽

Author(s):

D James Surmeier

Keyword(s):

Basal Ganglia ◽

Nonhuman Primates ◽

Functional Organization ◽

Medium Spiny Neurons ◽

Spiny Neurons

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

PLoS ONE ◽

10.1371/journal.pone.0033348 ◽

2012 ◽

Vol 7 (3) ◽

pp. e33348 ◽

Cited By ~ 40

Author(s):

Melissa L. Perreault ◽

Theresa Fan ◽

Mohammed Alijaniaram ◽

Brian F. O'Dowd ◽

Susan R. George

Keyword(s):

D2 Receptor ◽

Medium Spiny Neurons ◽

Spiny Neurons

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Origins of basal ganglia output signals in singing juvenile birds

Journal of Neurophysiology ◽

10.1152/jn.00635.2014 ◽

2015 ◽

Vol 113 (3) ◽

pp. 843-855 ◽

Cited By ~ 3

Author(s):

Morgane Pidoux ◽

Tejapratap Bollu ◽

Tori Riccelli ◽

Jesse H. Goldberg

Keyword(s):

Basal Ganglia ◽

Cell Types ◽

Medium Spiny Neurons ◽

Firing Patterns ◽

Spiny Neurons ◽

Corticostriatal Inputs ◽

Fast Spiking ◽

Output Neurons ◽

Cortical Inputs ◽

Complex Circuits

Across species, complex circuits inside the basal ganglia (BG) converge on pallidal output neurons that exhibit movement-locked firing patterns. Yet the origins of these firing patterns remain poorly understood. In songbirds during vocal babbling, BG output neurons homologous to those found in the primate internal pallidal segment are uniformly activated in the tens of milliseconds prior to syllable onsets. To test the origins of this remarkably homogenous BG output signal, we recorded from diverse upstream BG cell types during babbling. Prior to syllable onsets, at the same time that internal pallidal segment-like neurons were activated, putative medium spiny neurons, fast spiking and tonically active interneurons also exhibited transient rate increases. In contrast, pallidal neurons homologous to those found in primate external pallidal segment exhibited transient rate decreases. To test origins of these signals, we performed recordings following lesion of corticostriatal inputs from premotor nucleus HVC. HVC lesions largely abolished these syllable-locked signals. Altogether, these findings indicate a striking homogeneity of syllable timing signals in the songbird BG during babbling and are consistent with a role for the indirect and hyperdirect pathways in transforming cortical inputs into BG outputs during an exploratory behavior.

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Direct pathway neurons in mouse dorsolateral striatum in vivo receive stronger synaptic input than indirect pathway neurons

Journal of Neurophysiology ◽

10.1152/jn.00481.2019 ◽

2019 ◽

Vol 122 (6) ◽

pp. 2294-2303 ◽

Cited By ~ 4

Author(s):

Marko Filipović ◽

Maya Ketzef ◽

Ramon Reig ◽

Ad Aertsen ◽

Gilad Silberberg ◽

...

Keyword(s):

Membrane Potential ◽

Basal Ganglia ◽

Medium Spiny Neurons ◽

Indirect Pathway ◽

Potential Fluctuations ◽

Direct Pathway ◽

Spiny Neurons ◽

Total Input ◽

Membrane Potential Fluctuations

Striatal projection neurons, the medium spiny neurons (MSNs), play a crucial role in various motor and cognitive functions. MSNs express either D1- or D2-type dopamine receptors and initiate the direct-pathway (dMSNs) or indirect pathways (iMSNs) of the basal ganglia, respectively. dMSNs have been shown to receive more inhibition than iMSNs from intrastriatal sources. Based on these findings, computational modeling of the striatal network has predicted that under healthy conditions dMSNs should receive more total input than iMSNs. To test this prediction, we analyzed in vivo whole cell recordings from dMSNs and iMSNs in healthy and dopamine-depleted (6OHDA) anaesthetized mice. By comparing their membrane potential fluctuations, we found that dMSNs exhibited considerably larger membrane potential fluctuations over a wide frequency range. Furthermore, by comparing the spike-triggered average membrane potentials, we found that dMSNs depolarized toward the spike threshold significantly faster than iMSNs did. Together, these findings (in particular the STA analysis) corroborate the theoretical prediction that direct-pathway MSNs receive stronger total input than indirect-pathway neurons. Finally, we found that dopamine-depleted mice exhibited no difference between the membrane potential fluctuations of dMSNs and iMSNs. These data provide new insights into the question of how the lack of dopamine may lead to behavioral deficits associated with Parkinson’s disease. NEW & NOTEWORTHY The direct and indirect pathways of the basal ganglia originate from the D1- and D2-type dopamine receptor expressing medium spiny neurons (dMSNs and iMSNs). Theoretical results have predicted that dMSNs should receive stronger synaptic input than iMSNs. Using in vivo intracellular membrane potential data, we provide evidence that dMSNs indeed receive stronger input than iMSNs, as has been predicted by the computational model.

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