How Certain Movement Control Cells Go Into Overdrive and Cause Unwanted Movements in Parkinson’s

Background: Levodopa-induced dyskinesia (LID) is a common side effect of long-term dopamine replacement therapy in Parkinson’s disease, producing involuntary movements. The striatum integrates dopaminergic and glutamatergic input to control movement, but the cellular mechanisms that lead to the abnormal activation of specific neuronal subtypes during LID remain unclear.

Hypothesis: This study hypothesized that striatal direct pathway medium spiny neurons (dMSNs) activated during dyskinesia possess heightened dopamine sensitivity and excitatory synaptic drive, resulting in excessive levodopa-evoked firing that contributes to abnormal motor activity.

Methods: The authors used a FosTRAP mouse model of LID to label neurons activated during dyskinesia and applied electrophysiological, optogenetic and tracing methods to characterize them. Monosynaptic rabies tracing was performed to map presynaptic inputs, and brain sections were reconstructed and registered to the CCF v3 using NeuroInfo for automated cell detection and quantification. Whole-cell recordings were conducted to assess excitability and synaptic strength, and fluorescent in situ hybridization quantified dopamine receptor and prodynorphin expression.

Results: TRAPed dMSNs exhibited markedly higher firing rates after levodopa administration compared with other striatal neurons. They showed increased frequency of miniature excitatory postsynaptic currents, decreased paired-pulse ratios and stronger excitatory inputs from motor cortex and thalamus. These neurons also displayed elevated excitability in response to D1 receptor stimulation and higher D1 receptor and prodynorphin mRNA levels.

Conclusions: TRAPed dMSNs represent a dyskinesia-associated subpopulation with enhanced dopamine signaling and excitatory input, which together drive excessive firing and underlie the pathophysiology of levodopa-induced dyskinesia.

Ryan MB, Girasole AE, Flores AJ, Twedell EL, McGregor MM, Brakaj R, Paletzki RF, Hnasko TS, Gerfen CR, Nelson AB. Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input. Cell Rep 2024;43(8):114483. doi: 10.1016/j.celrep.2024.114483.