Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment disrupt frontostriatal plasticity

Sarah Chevalier, Mélina Decourt, Maureen Francheteau, François Nicol, Anaïs Balbous, Pierre-Olivier Fernagut, Marianne Benoit-Marand
npj Parkinson's Disease. 2024-09-09; 10(1):
DOI: 10.1038/s41531-024-00781-4

1. NPJ Parkinsons Dis. 2024 Sep 9;10(1):169. doi: 10.1038/s41531-024-00781-4.

Alpha-synuclein-induced nigrostriatal degeneration and pramipexole treatment
disrupt frontostriatal plasticity.

Chevalier S(#)(1), Decourt M(#)(1), Francheteau M(1), Nicol F(1), Balbous
A(1)(2), Fernagut PO(1), Benoit-Marand M(3).

Author information:
(1)Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales
et Cliniques, U1084, Poitiers, France.
(2)CHU de Poitiers, Poitiers, France.
(3)Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales
et Cliniques, U1084, Poitiers, France. .
(#)Contributed equally

Parkinson’s disease is characterized by the degeneration of substantia nigra
pars compacta (SNc) dopaminergic neurons, leading to motor and cognitive
symptoms. Numerous cellular and molecular adaptations following
neurodegeneration or dopamine replacement therapy (DRT) have been described in
motor networks but little is known regarding associative basal ganglia loops.
This study investigated the contributions of nigrostriatal degeneration and
pramipexole (PPX) on neuronal activity in the orbitofrontal cortex (OFC),
frontostriatal plasticity, and markers of synaptic plasticity. Bilateral
nigrostriatal degeneration was induced by viral-mediated expression of human
mutated alpha-synuclein in the SNc. Juxtacellular recordings were performed in
anesthetized rats to evaluate neuronal activity in the OFC. Recordings in the
dorsomedial striatum (DMS) were performed, and spike probability in response to
OFC stimulation was measured before and after high-frequency stimulation (HFS).
Post-mortem analysis included stereological assessment of nigral
neurodegeneration, BDNF and TrkB protein levels. Nigrostriatal neurodegeneration
led to altered firing patterns of OFC neurons that were restored by PPX. HFS of
the OFC led to an increased spike probability in the DMS, while dopaminergic
loss had the opposite effect. PPX led to a decreased spike probability following
HFS in control rats and failed to counteract the effect of dopaminergic
neurodegeneration. These alterations were associated with decreased levels of
BDNF and TrkB in the DMS. This study demonstrates that nigral dopaminergic loss
and PPX both contribute to alter frontostriatal transmission, precluding
adequate information processing in associative basal ganglia loops as a gateway
for the development of non-motor symptoms or non-motor side effects of DRT.

DOI: 10.1038/s41531-024-00781-4
PMCID: PMC11385550
PMID: 39251645

Conflict of interest statement: The authors declare no competing interests.
Financial disclosure for the preceding 12 months: S.C., M.D., F.N., A.B. and
M.F.: none. M.B.M. has received grant support from IRESP and Fondation de
France. P.O.F. has received grant support from Agence Nationale de la Recherche
and Fondation Maladies Rares.