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Angela Cenci Nilsson"Maladaptive plasticity in L-DOPA-induced dyskinesia: what, where, and why?"

Abstract :

The development of L-DOPA-induced dyskinesia (LID) is attributed to plastic responses triggered by dopamine (DA) receptor stimulation in the parkinsonian brain. This lecture will present studies performed in our laboratory to uncover different levels of maladaptive brain plasticity in LID. Rodents developing dyskinesia on chronic L-DOPA treatment show abnormal patterns of signaling pathway activation and synaptic plasticity in striatal neurons. In addition, these animals show a gene expression profile indicative of structural cellular plasticity, including pronounced upregulation of genes involved in extracellular matrix remodeling, neurite extension, synaptic vesicle trafficking, and endothelial and cellular proliferation. Accordingly, morphological investigations reveal pronounced structural changes that affect both neurons and non-neuronal components in the basal ganglia. The structural and functional adaptations induced by L-DOPA can be viewed as an attempt to meet increased metabolic demands, boost cellular defense mechanisms, and maintain synaptic homeostasis. By acting in a non-physiological manner on a diseased substrate, such adaptations, however, achieve a dysfunctional outcome, predisposing to the appearance of dyskinesia and other complications of dopaminergic therapies.

Selected publications

Rylander D, Parent M, O'Sullivan SS, Dovero S, Lees AJ, Bezard E, Descarries L, Cenci MA (2010) Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia. Ann Neurol 68:619-628.
Rylander D, Iderberg H, Li Q, Dekundy A, Zhang J, Li H, Baishen R, Danysz W, Bezard E, Cenci MA (2010) A mGluR5 antagonist under clinical development improves L-DOPA-induced dyskinesia in parkinsonian rats and monkeys. Neurobiol Dis 39:352-361.

 Lindgren HS, Andersson DR, Lagerkvist S, Nissbrandt H, Cenci MA (2010) L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson's disease: temporal and quantitative relationship to the expression of dyskinesia. J Neurochem 112:1465-1476.

Erwan Bézard , directeur de l'IMN