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Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE250364 | GEO | 2023/12/31

REPOSITORIES: GEO

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Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia II

Project description:L-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine replacement therapy with L-DOPA for the treatment of Parkinson disease (PD). We found repeated L-DOPA exposure induces unique transcriptional behavior in striatal neurons that is associated with the development of dyskinetic behaviors. These results suggest the development of a long-term neuronal engram underlying the persistence of LID .

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Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia I

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Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia

Project description:Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia

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Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia I

Project description:Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia I

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Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia II

Project description:Differential activation states of direct pathway striatal output neurons associated with the development of L-DOPA-induced dyskinesia II

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Differential innervation of direct- and indirect-pathway striatal projection neurons.

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Cell type-specific plasticity of striatal projection neurons in parkinsonism and L-DOPA-induced dyskinesia.

Project description:The striatum is widely viewed as the fulcrum of pathophysiology in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In these disease states, the balance in activity of striatal direct pathway spiny projection neurons (dSPNs) and indirect pathway spiny projection neurons (iSPNs) is disrupted, leading to aberrant action selection. However, it is unclear whether countervailing mechanisms are engaged in these states. Here we report that iSPN intrinsic excitability and excitatory corticostriatal synaptic connectivity were lower in PD models than normal; L-DOPA treatment restored these properties. Conversely, dSPN intrinsic excitability was elevated in tissue from PD models and suppressed in LID models. Although the synaptic connectivity of dSPNs did not change in PD models, it fell with L-DOPA treatment. In neither case, however, was the strength of corticostriatal connections globally scaled. Thus, SPNs manifested homeostatic adaptations in intrinsic excitability and in the number but not strength of excitatory corticostriatal synapses.

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Excessive Firing of Dyskinesia-Associated Striatal Direct Pathway Neurons is Gated by Dopamine and Excitatory Synaptic Input

Project description: Not available

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Hyperactive Response of Direct Pathway Striatal Projection Neurons to L-dopa and D1 Agonism in Freely Moving Parkinsonian Mice.

Project description:Dopamine (DA) profoundly stimulates motor function as demonstrated by the hypokinetic motor symptoms in Parkinson's disease (PD) and by the hyperkinetic motor side effects during dopaminergic treatment of PD. Dopamine (DA) receptor-bypassing, optogenetics- and chemogenetics-induced spike firing of striatal DA D1 receptor (D1R)-expressing, direct pathway medium spiny neurons (dSPNs or dMSNs) promotes movements. However, the endogenous D1R-mediated effects, let alone those of DA replacement, on dSPN spike activity in freely-moving animals is not established. Here we show that using transcription factor Pitx3 null mutant (Pitx3Null) mice as a model for severe and consistent DA denervation in the dorsal striatum in Parkinson's disease, antidromically identified striatonigral neurons (D1R-expressing dSPNs) had a lower baseline spike firing rate than that in DA-intact normal mice, and these neurons increased their spike firing more strongly in Pitx3Null mice than in WT mice in response to injection of L-dopa or the D1R agonist, SKF81297; the increase in spike firing temporally coincided with the motor-stimulating effects of L-dopa and SKF81297. Taken together, these results provide the first evidence from freely moving animals that in parkinsonian striatum, identified behavior-promoting dSPNs become hyperactive upon the administration of L-dopa or a D1 agonist, likely contributing to the profound dopaminergic motor stimulation in parkinsonian animals and PD patients.

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