Levodopa Causes Striatal Cholinergic Interneuron Burst-Pause Activity in Parkinsonian Mice.
Mov Disord
; 36(7): 1578-1591, 2021 07.
Article
en En
| MEDLINE
| ID: mdl-33547844
ABSTRACT
BACKGROUND:
Enhanced striatal cholinergic interneuron activity contributes to the striatal hypercholinergic state in Parkinson's disease (PD) and to levodopa-induced dyskinesia. In severe PD, dyskinesia and motor fluctuations become seriously debilitating, and the therapeutic strategies become scarce. Given that the systemic administration of anticholinergics can exacerbate extrastriatal-related symptoms, targeting cholinergic interneurons is a promising therapeutic alternative. Therefore, unraveling the mechanisms causing pathological cholinergic interneuron activity in severe PD with motor fluctuations and dyskinesia may provide new molecular therapeutic targets.METHODS:
We used ex vivo electrophysiological recordings combined with pharmacological and morphological studies to investigate the intrinsic alterations of cholinergic interneurons in the 6-hydroxydopamine mouse model of PD treated with levodopa.RESULTS:
Cholinergic interneurons exhibit pathological burst-pause activity in the parkinsonian "off levodopa" state. This is mediated by a persistent ligand-independent activity of dopamine D1/D5 receptor signaling, involving a cyclic adenosine monophosphate (cAMP) pathway. Dysregulation of membrane ion channels that results in increased inward-rectifier potassium type 2 (Kir2) and decreased leak currents causes the burst pause activity, which can be dampened by pharmacological inhibition of intracellular cAMP. A single challenge with a dyskinetogenic dose of levodopa is sufficient to induce persistent cholinergic interneuron burst-pause firing.CONCLUSION:
Our data unravel a mechanism causing aberrant cholinergic interneuron burst-pause activity in parkinsonian mice treated with levodopa. Targeting D5-cAMP signaling and the regulation of Kir2 and leak channels may alleviate parkinsonism and dyskinesia by restoring normal cholinergic interneuron function. © 2021 International Parkinson and Movement Disorder Society.Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Levodopa
/
Cuerpo Estriado
Tipo de estudio:
Etiology_studies
Límite:
Animals
Idioma:
En
Revista:
Mov Disord
Asunto de la revista:
NEUROLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Argentina