TY - JOUR

T1 - Biophysical Modeling of Dopaminergic Denervation Landscapes in the Striatum Reveals New Therapeutic Strategy

AU - Heltberg, Mathias L.

AU - Awada, Hussein N.

AU - Lucchetti, Alessandra

AU - Jensen, Mogens H.

AU - Dreyer, Jakob K.

AU - Rasmussen, Rune N.

N1 - Erratum. DOI: 10.1523/ENEURO.0147-22.2022 Publisher Copyright: Copyright © 2022 Heltberg et al.

PY - 2022

Y1 - 2022

N2 - Parkinson's disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete. In this study, we investigate this, by characterizing the dopaminergic landscape in healthy and denervated striatum, using biophysical modeling. Based on currently proposed mechanisms, we model three distinct denervation patterns, and show how this affect the dopaminergic network. Depending on the denervation pattern, we show how local and global differences arise in the activity of striatal neurons. Finally, we use the mathematical formalism to suggest a cellular strategy for maintaining normal dopamine (DA) signaling following neuronal denervation. This strategy is characterized by dual enhancement of both the release and uptake capacity of DA in the remaining neurons. Overall, our results derive a new conceptual framework for the impaired dopaminergic signaling related to PD and offers testable predictions for future research directions.

AB - Parkinson's disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete. In this study, we investigate this, by characterizing the dopaminergic landscape in healthy and denervated striatum, using biophysical modeling. Based on currently proposed mechanisms, we model three distinct denervation patterns, and show how this affect the dopaminergic network. Depending on the denervation pattern, we show how local and global differences arise in the activity of striatal neurons. Finally, we use the mathematical formalism to suggest a cellular strategy for maintaining normal dopamine (DA) signaling following neuronal denervation. This strategy is characterized by dual enhancement of both the release and uptake capacity of DA in the remaining neurons. Overall, our results derive a new conceptual framework for the impaired dopaminergic signaling related to PD and offers testable predictions for future research directions.

KW - biophysics

KW - Parkinson’s disease

U2 - 10.1523/ENEURO.0458-21.2022

DO - 10.1523/ENEURO.0458-21.2022

M3 - Journal article

C2 - 35165198

AN - SCOPUS:85125682685

VL - 9

JO - eNeuro

JF - eNeuro

SN - 2373-2822

IS - 2

ER -