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Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

ABSTRACT: Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. However, the mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we test this in a translational mouse imaging study using a ketamine model. Mice were treated with sub-chronic ketamine (30mg/kg) or saline followed by in-vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open field test. In-vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d=2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of cortical and ventral subiculum PV interneurons. Sub-chronic ketamine reduced PV expression in these neurons. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1), significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, and suggest an underlying neurocircuit involving PV interneuron hypofunction in frontal cortex and hippocampus as well as activation of midbrain dopamine neurons. A novel TAAR1 agonist reversed the dopaminergic alterations suggesting a therapeutic mechanism for targeting presynaptic dopamine dysfunction in patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE138802 | GEO | 2021/02/16

REPOSITORIES: GEO

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Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease. To profile the cell-type-specific responses of striatal spiny projection neurons (SPNs) to striatal dopamine depletion, we conducted TRAP analysis of the two major classes of these neurons: dSPNs that express the dopamine receptor 1a (Drd1a), and iSPNs that express the dopamine receptor 2 (Drd2). To disrupt dopamine innervation to both of these SPN populations that reside in the striatum, we injected the neurotoxin 6-hydroxydopamine (6-OHDA), unilaterally, in the medial forebrain bundle (MFB) in hemizygous Drd1-TRAP and Drd2-TRAP adult (9-14 weeks) male mice (kept on a C57BL/6J genetic background). This lesion procedure causes nigral dopamine cell death within a few days, along with a widespread and near-complete loss of dopaminergic innervation to the entire dorsal striatum on one side of the brain (a hemiparkinsonian model). We first examined the effects of dopamine depletion alone, compared to a mock lesion (ascorbate / saline injected). We then examined the effects of chronic levodopa treatment upon the molecular profiles of dopamine- depleted dSPNs and iSPNs, with two dose regimens. The ‘high-dose’ L-DOPA regimen (3 mg/kg on days 1-3, followed by 6 mg/kg on days 4-9) was expected to induce severe dyskinesia in all MFB-lesioned mice. The low-dose L-DOPA regimen (1 mg/kg on days 1-3, followed by 2 mg/kg on days 4-9) was expected to reverse limb use asymmetry without causing conspicuous dyskinesias. To equalize the effects of stress and handling across all groups, including control groups, all mice were equally handled and thus received saline injections when not receiving levodopa injections. Each treatment group contained 7-10 replicates. TRAP-purified mRNAs from either Drd1a- or Drd2-expressing SPNs were reverse-transcribed, amplified, and used to interrogate Affymetrix 430_2.0 GeneChip microarrays.

Project description:Yapo2017- cAMP/PKA signalling in D1 dopamine receptor expressing medium-spiny neurons This model is described in the article: Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons. Yapo C, Nair AG, Clement L, Castro LR, Hellgren Kotaleski J, Vincent P. J. Physiol. (Lond.) 2017 Aug; : Abstract: The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of dopamine effect on intracellular signalling remains poorly understood. We used genetically-encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation level, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D1 or D2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D2 than on D1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate in a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of Protein Phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a "tone-sensing" mode, allowing them to detect transient dips in basal dopamine. Overall, our results show that D2 MSNs may sense much more complex patterns of dopamine than previously thought. This article is protected by copyright. All rights reserved. This model is hosted on BioModels Database and identified by: MODEL1701170000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Yapo2017 - A2AR/cAMP/PKA signalling in D2 dopamine receptor expressing medium-spiny neurons This model is described in the article: Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons. Yapo C, Nair AG, Clement L, Castro LR, Hellgren Kotaleski J, Vincent P. J. Physiol. (Lond.) 2017 Aug; : Abstract: The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of dopamine effect on intracellular signalling remains poorly understood. We used genetically-encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation level, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D1 or D2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D2 than on D1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate in a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of Protein Phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a "tone-sensing" mode, allowing them to detect transient dips in basal dopamine. Overall, our results show that D2 MSNs may sense much more complex patterns of dopamine than previously thought. This article is protected by copyright. All rights reserved. This model is hosted on BioModels Database and identified by: MODEL1701170001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Schizophrenia is a chronic mental illness that is among the world’s top twenty causes of years lost to disability according to the global burden of disease 2019 (10.1016/S0140-6736(20)30925-9). Positive symptoms, including hallucinations and delusions in schizophrenia, often improved with conventional antipsychotic medication, which exerts its therapeutic effects mainly by antagonizing the dopamine D2 receptors. Haloperidol was one of the first antipsychotics to be approved by the FDA, and it is since then widely used for the treatment of psychotic disorders including schizophrenia. Despite its high affinity for dopamine D2 receptors, it has been shown that haloperidol interacts with other receptors, such as dopamine D3 and D4 receptors, α-adrenergic receptor 1 and to some extent 5HT2A. Dopaminergic dysfunction is known for decades to be involved in the pathophysiology of schizophrenia, but only recently has the striatum been implicated in such devasting disorder. The dorsal striatum is a brain region involved in motor, cognitive and motivational functions, highly impacted by antipsychotic drugs. Particularly, it is well-recognized that chronic haloperidol administration has a tremendous impact on striatal synaptic plasticity, by changing the volume of dorsal striatum, the number of striatal neurons and the synaptic morphology, both in humans and rodents. Despite the overwhelming evidence correlating chronic haloperidol administration with striatum alterations, so far, the exact striatal synaptic mechanism by which haloperidol exerts its beneficial effects remains unclear. Although dopamine D2 receptor blockade can be achieved within hours after haloperidol administration, the onset of action is delayed by weeks. Thus, it is crucial to better understand the neuronal mechanism behind the delayed clinical effects of haloperidol to improve the treatment outcome. Using proteomic analysis and whole-cell patch-clamp recordings (Figure 1), we demonstrate for the first time a possible mechanism by which haloperidol may be contributing to its beneficial long-term therapeutic effect. Specifically, we demonstrate that modulation of D2-MSNs by chronic haloperidol administration leads to a slow remodeling of D1-neurons that may be responsible for its positive therapeutic effects.

Project description:Nair2016 - Integration of calcium and dopamine signals by D1R-expressing medium-sized spiny neurons This model is described in the article: Role of DARPP-32 and ARPP-21 in the Emergence of Temporal Constraints on Striatal Calcium and Dopamine Integration. Nair AG, Bhalla US, Hellgren Kotaleski J. PLoS Comput. Biol. 2016 Sep; 12(9): e1005080 Abstract: In reward learning, the integration of NMDA-dependent calcium and dopamine by striatal projection neurons leads to potentiation of corticostriatal synapses through CaMKII/PP1 signaling. In order to elicit the CaMKII/PP1-dependent response, the calcium and dopamine inputs should arrive in temporal proximity and must follow a specific (dopamine after calcium) order. However, little is known about the cellular mechanism which enforces these temporal constraints on the signal integration. In this computational study, we propose that these temporal requirements emerge as a result of the coordinated signaling via two striatal phosphoproteins, DARPP-32 and ARPP-21. Specifically, DARPP-32-mediated signaling could implement an input-interval dependent gating function, via transient PP1 inhibition, thus enforcing the requirement for temporal proximity. Furthermore, ARPP-21 signaling could impose the additional input-order requirement of calcium and dopamine, due to its Ca2+/calmodulin sequestering property when dopamine arrives first. This highlights the possible role of phosphoproteins in the temporal aspects of striatal signal transduction. This model is hosted on BioModels Database and identified by: MODEL1603270000. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Mesocorticolimbic circuit mechanisms underlying the effects of ketamine on dopamine: a translational imaging study

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