Zooming in on the small: The plasticity of striatal dendritic spines in l‐DOPA–Induced dyskinesia

Abstract

The spiny dendrites of striatal projection neurons integrate synaptic inputs of different origins to regulate movement. It has long been known that these dendrites lose spines and display atrophic features in Parkinson's disease (PD), but the significance of these morphological changes has remained unknown. Some recent studies reveal a remarkable structural plasticity of striatal spines in parkinsonian rodents treated with L-3,4-dihydroxyphenylalanine (L-DOPA), and they demonstrate an association between this plasticity and the development of dyskinesia. These studies used different approaches and animal models, which possibly explains why they emphasize different plastic changes as being most closely linked to dyskinesia (such as a growth of new spines in neurons of the indirect pathway, or a loss of spines in neurons of the direct pathway, or the appearance of spines with aberrant synaptic features). Clearly, further investigations are required to reconcile these intriguing findings and integrate them in a coherent pathophysiological model. Nevertheless, these studies may mark the beginning of a new era for dyskinesia research. In addition to addressing neurochemical and molecular events that trigger involuntary movements, there is a need to better understand the long-lasting structural reorganization of cells and circuits that maintain the brain in a "dyskinesia-prone" state. This may lead to the identification of new efficacious approaches to prevent the complications of dopaminergic therapies in PD.

Clinical Outcomes in Patients with Parkinson's Disease Treated with a Monoamine Oxidase Type‐B inhibitor: A Cross‐Sectional, Cohort Study

“…In PD, alterations that occur in striatal cells of the dopamine‐denervated striatum are dystrophic changes in the dendrites of MSNs, with a loss of dendritic length and dendritic spine number. Morphologic changes in MSNs are associated with development of dyskinesias . The MAOB‐I, rasagiline, has been shown to possess dendritic remodeling properties by increasing the length and the number of dendritic branch points .…”

On the neuronal circuitry mediating l-DOPA-induced dyskinesia

“…This hypothesis marked the start of a new era in basal ganglia research because it was seminal to a vast literature searching for distinct roles of striatal output pathways in the modulation of physiological or pathological behaviours. Since dSPNs and iSPNs express distinct complements of membrane receptors and signaling molecules, dissecting the relative contribution of these neurons to parkinsonism and LID appears essential to develop optimal pharmacological therapies (Fieblinger and Cenci 2015). …”

Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease

“…LIDs have been associated with structural changes in spine morphology in the striatum. This includes the appearance of aberrant spines, the development of new spines or a loss of existing spines in neurons of the corticostriatal, direct and/or indirect pathways [141–144]. Nicotine may restore aberrant signaling that contributes to LIDs by modulating spine formation/morphology as it is well known to modulate neuronal morphology via an interaction at α7 nAChRs [39, 41, 145].…”