Biology subjects

Ryan, M. B.

Publications and source records attributed to Ryan, M. B..

2 recordsLinked to original sources

bioRxiv2025

Repetitive Levodopa Treatment Drives Cell Type-Specific Striatal Adaptations Associated With Progressive Dyskinesia in Parkinsonian Mice

The use of levodopa to manage Parkinsons disease (PD) symptoms leads to levodopa-induced dyskinesia (LID) and other motor fluctuations, which worsen with disease progression and repeated treatment. Aberrant activity of striatal D1- and D2-expressing medium spiny neurons (D1-/D2-MSNs) underlies LID, but the mechanisms driving its progression remain unclear. Using the 6-OHDA mouse model of PD/LID, we combined in vivo and ex vivo recordings to isolate the effect of repeated treatment in LID worsening and other motor fluctuation-related phenotypes. We found that LID worsening is linked to potentiation of levodopa-evoked responses in both D1-/D2-MSNs, independent of changes in dopamine release or MSN intrinsic excitability. Instead, strengthening of glutamatergic synapses onto D1-MSNs emerged as a key driver. Moreover, we found changes in D2-MSN activity that specifically influenced LID duration, potentially contributing to motor fluctuations, which paralleled a reduction in D2R sensitivity. These findings reveal striatal adaptations contributing to worsening of levodopa-related complications.

neuroscience↗

bioRxiv2022

Excessive Firing of Dyskinesia-Associated Striatal Direct Pathway Neurons is Gated By Dopamine and Excitatory Synaptic Input

The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions, but the precise mechanisms remain unclear. One way to study action selection is when it breaks down. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinsons disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs). In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. This activation is likely to be driven by two cellular mechanisms we identified through ex vivo electrophysiology: higher sensitivity to dopamine and stronger excitatory input from the motor cortex and thalamus. Together, these findings suggest how intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.

neuroscience↗