Distinct patterns of dyskinetic and dystonic features following D1 or D2 receptor stimulation in a mouse model of parkinsonism

Andreoli, Laura; Abbaszadeh, Morteza; Cao, Xiao Yan; Cenci, M. Angela

doi:10.1016/j.nbd.2021.105429

Cited by 23 publications

(20 citation statements)

References 85 publications

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“…S3C). 39,46 We found that increasing SNr neuron activity in ChR2‐mice with blue laser light at 25–100 Hz significantly suppressed AIM scores (Fig. 2A; Supporting Information Video S1).…”

Section: Resultsmentioning

confidence: 87%

“…After LID testing at 40 minutes after l ‐dopa injection, we tested stepping to assess whether ChR2 stimulation altered stepping improvement by l ‐dopa. We did not score orofacial AIMs because of the inability to accurately assess them in our videos, especially in the larger open‐field arena (Supporting Information Video S1) and because changes in orofacial AIMs scores mirror limb AIMs when D1‐ or D2‐dopamine receptors are blocked during LID 39 …”

Section: Methodsmentioning

confidence: 99%

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Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia

Alberico

et al. 2023

Movement Disorders

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BackgroundLong‐term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa‐induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID.ObjectiveThe objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model.MethodsWe expressed Cre‐recombinase activated channelrhodopsin‐2 (ChR2) or halorhodopsin adeno‐associated virus‐2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat‐IRES‐Cre mice in a 6‐hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open‐field locomotion were used to assess akinesia and LID to test the effect of SNr modulation.ResultsAkinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation.ConclusionsModulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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Section: Resultsmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia

Alberico

et al. 2023

Movement Disorders

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“…It is interesting to consider that the strongest NBG oscillations were detected in motor regions related to forelimb movements, which are mainly engaged in fast hyperkinetic forms of dyskinetic behaviour in this animal model [36,62]. After all treatments, NBG oscillations were markedly less pronounced in motor regions controlling trunk movements, which are engaged in slow twisting movements [36,62]. Additionally, it is worth noting that treatment with the D2 receptor agonist did not induce NBG oscillations in the trunk motor area.…”

Section: Effects Of D1 and D2 Receptor Agonists On Nbg Activitymentioning

confidence: 83%

“…In this area, the induction of NBG oscillations was considerably lower than in frontal motor cortical areas controlling forelimb movements, and this rhythm was not even detectable following D2 stimulation. It is interesting to consider that the strongest NBG oscillations were detected in motor regions related to forelimb movements, which are mainly engaged in fast hyperkinetic forms of dyskinetic behaviour in this animal model [36,62]. After all treatments, NBG oscillations were markedly less pronounced in motor regions controlling trunk movements, which are engaged in slow twisting movements [36,62].…”

Section: Effects Of D1 and D2 Receptor Agonists On Nbg Activitymentioning

confidence: 85%

“…Another aspect to consider is the relative representation of fast hyperkinetic vs. slow dystonic-like components in the involuntary movements. Indeed, our recent studies in L-DOPA-naïve 6-OHDA-lesioned mice show that, in the absence of D1 stimulation, D2 receptors selectively mediate dystonic forms of dyskinesia [62]. Interestingly, an association between dystonic motor manifestations and theta oscillations has been found in primary dystonia patients using pallidal recordings (reviewed in [9]).…”

Section: Effects Of D1 and D2 Receptor Agonists On Theta Oscillatory ...mentioning

confidence: 99%

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Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia

Skovgård

Barrientos²,

Petersson³

et al. 2023

Neurotherapeutics

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L-DOPA-induced dyskinesia (LID) in Parkinson’s disease has been linked to oscillatory neuronal activities in the cortico-basal ganglia network. We set out to examine the pattern of cortico-basal ganglia oscillations induced by selective agonists of D1 and D2 receptors in a rat model of LID. Local field potentials were recorded in freely moving rats using large-scale electrodes targeting three motor cortical regions, dorsomedial and dorsolateral striatum, external globus pallidus, and substantial nigra pars reticulata. Abnormal involuntary movements were elicited by the D1 agonist SKF82958 or the D2 agonist sumanirole, while overall motor activity was quantified using video analysis (DeepLabCut). Both SKF82958 and sumanirole induced dyskinesia, although with significant differences in temporal course, overall severity, and body distribution. The D1 agonist induced prominent narrowband oscillations in the high gamma range (70–110 Hz) in all recorded structures except for the nigra reticulata. Additionally, the D1 agonist induced strong functional connectivity between the recorded structures and the phase analysis revealed that the primary motor cortex (forelimb area) was leading a supplementary motor area and striatum. Following treatment with the D2 agonist, narrowband gamma oscillations were detected only in forelimb motor cortex and dorsolateral striatum, while prominent oscillations in the theta band occurred in the globus pallidus and nigra reticulata. Our results reveal that the dyskinetic effects of D1 and D2 receptor agonists are associated with distinct patterns of cortico-basal ganglia oscillations, suggesting a recruitment of partially distinct networks.

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Activation of dopamine 2 receptors modulates glutamate decarboxylases 65 and 67 during stroke recovery in mice

Talhada,

Nilsson,

Walser

et al. 2023

Neuroprotection

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BackgroundsTreatment with levodopa enhances recovery of lost neurological functions in preclinical stroke models and patients. Here, we studied whether dopamine signaling modulates GABAergic neurotransmission in parvalbumin‐positive interneurons after experimental stroke.MethodsFollowing block randomization, mice were subjected to experimental stroke induced by photothrombosis (PT). Two days after the insult, mice were treated either with the D1 receptor antagonist by R(+)‐SCH‐23390 (0.1 mg/kg), the selective D1 receptor agonist (R)‐(+)‐SKF‐38393 hydrochloride (1 mg/kg), the D2 receptor agonist R(−)‐2,10,11‐trihydroxy‐N‐propyl‐noraporphine hydrobromide hydrate (TNPA) (1 mg/kg), the D2 receptor antagonist S‐(−)‐eticlopride hydrochloride (0.3 mg/kg), or vehicle (saline) by daily intraperitoneal injection for five consecutive days, respectively. Recovery of function was assessed by paw placement and foot fault test before and on Days 2 and 7 after surgery.ResultsMice treated with TNPA showed a statistically significant improvement of recovery compared to all other treatment conditions. Synthesis of gamma‐aminobutyric acid (GABA) was quantified by levels of full‐length and cleaved glutamate acid decarboxylase 67 and 65 (GAD65 and GAD67) in the peri‐infarct area and homotypic regions of the contralateral cortex. Compared to the other treatments, TNPA significantly reduced the level of the GAD67 isoform both in the ischemic and contralateral hemispheres. Levels of GAD65 were found significantly higher in the contralateral hemisphere in TNPA‐treated mice after PT accompanied by an increase in the 58 kDa‐truncated form.ConclusionOur results point toward reduced GABA synthesis in a D2 receptor‐mediated mechanism possibly contributing to counteract functional inhibition after stroke.

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Distinct patterns of dyskinetic and dystonic features following D1 or D2 receptor stimulation in a mouse model of parkinsonism

Cited by 23 publications

References 85 publications

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia

Distinctive Effects of D1 and D2 Receptor Agonists on Cortico-Basal Ganglia Oscillations in a Rodent Model of L-DOPA-Induced Dyskinesia

Activation of dopamine 2 receptors modulates glutamate decarboxylases 65 and 67 during stroke recovery in mice

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