PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking
Gregory Porras, Amandine Berthet, Benjamin Dehay, Qin Li, Laurent Ladepeche, Elisabeth Normand, Sandra Dovero, Audrey Martinez, Evelyne Doudnikoff, Marie-Laure Martin-Négrier, Qin Chuan, Bertrand Bloch, Daniel Choquet, Eric Boué-Grabot, Laurent Groc, Erwan Bezard
Gregory Porras, Amandine Berthet, Benjamin Dehay, Qin Li, Laurent Ladepeche, Elisabeth Normand, Sandra Dovero, Audrey Martinez, Evelyne Doudnikoff, Marie-Laure Martin-Négrier, Qin Chuan, Bertrand Bloch, Daniel Choquet, Eric Boué-Grabot, Laurent Groc, Erwan Bezard
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Research Article Genetics

PSD-95 expression controls l-DOPA dyskinesia through dopamine D1 receptor trafficking

Abstract

l-DOPA–induced dyskinesia (LID), a detrimental consequence of dopamine replacement therapy for Parkinson’s disease, is associated with an alteration in dopamine D1 receptor (D1R) and glutamate receptor interactions. We hypothesized that the synaptic scaffolding protein PSD-95 plays a pivotal role in this process, as it interacts with D1R, regulates its trafficking and function, and is overexpressed in LID. Here, we demonstrate in rat and macaque models that disrupting the interaction between D1R and PSD-95 in the striatum reduces LID development and severity. Single quantum dot imaging revealed that this benefit was achieved primarily by destabilizing D1R localization, via increased lateral diffusion followed by increased internalization and diminished surface expression. These findings indicate that altering D1R trafficking via synapse-associated scaffolding proteins may be useful in the treatment of dyskinesia in Parkinson’s patients.

Authors

Gregory Porras, Amandine Berthet, Benjamin Dehay, Qin Li, Laurent Ladepeche, Elisabeth Normand, Sandra Dovero, Audrey Martinez, Evelyne Doudnikoff, Marie-Laure Martin-Négrier, Qin Chuan, Bertrand Bloch, Daniel Choquet, Eric Boué-Grabot, Laurent Groc, Erwan Bezard

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Figure 5

PSD-95 knockdown or peptide disrupting PSD-95–D1R interaction alters D1R surface content and dynamics on cultured striatal neurons.

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PSD-95 knockdown or peptide disrupting PSD-95–D1R interaction alters D1R...
(A and B) Immunostaining of surface D1R (A) showed a significant decrease in surface D1R in shPSD neurons (B). Scale bar: 16 μm. *P < 0.05. (C) Representative trajectories of surface D1Rs labeled with a single QD-antibody complex (inset) at the surface of a PSD-95–expressing neuron. A fraction rapidly diffused along dendrites and explored large areas (arrows), whereas others diffused in a confined area (arrowheads). Scale bars: 4 μm (left); 200 nm (right). (D) Representative trajectories of surface D1R on a Homer1c-GFP–expressing neuron. Also shown are distributions (median and 25%–75% IQR) of the instantaneous diffusion coefficient of surface D1Rs inside and outside the PSD area. Scale bar: 2 μm. *P < 0.05. (E) Representative trajectories of surface D1Rs on a shPSD-expressing striatal neuron. Scale bar: 4 μm. (F) Cumulative distribution of the instantaneous diffusion coefficient of surface D1Rs, starting from the percentage of immobile receptors. (G) Corresponding distributions of the instantaneous diffusion coefficient of surface D1Rs. *P < 0.05. (H) The relationship between mean square displacement (MSD) and time of surface D1R trajectories was not linear (dotted line denotes free diffusion), adopting negative curvature, characteristic of confined behavior (Kolmogorov-Smirnov test). (I and J) Representative trajectories (I) and distributions of the instantaneous diffusion coefficient (J) of surface D1Rs in the presence of TAT-D1-SCR or TAT-D1-CT. Scale bar: 5 μm. *P < 0.05.