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
Author Information
Sarah Chevalier: Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, U1084, Poitiers, France.
Mélina Decourt: Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, U1084, Poitiers, France.
Maureen Francheteau: Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, U1084, Poitiers, France.
François Nicol: Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, U1084, Poitiers, France.
Anaïs Balbous: Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, U1084, Poitiers, France.
Pierre-Olivier Fernagut: Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, U1084, Poitiers, France. ORCID
Marianne Benoit-Marand: Université de Poitiers, INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, U1084, Poitiers, France. marianne.benoit.marand@univ-poitiers.fr. ORCID
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.
References
Neurobiol Dis. 2022 Jun 1;167:105674
[PMID: 35245676]
