Excessive firing of dyskinesia-associated striatal direct pathway neurons is gated by dopamine and excitatory synaptic input
Michael B. Ryan,
Allison E. Girasole,
Andrew J. Flores,
Emily L. Twedell,
Matthew M. McGregor,
Rea Brakaj,
Ronald F. Paletzki,
Thomas S. Hnasko,
Charles R. Gerfen,
Alexandra B. Nelson
Affiliations
Michael B. Ryan
Neuroscience Graduate Program, UCSF, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA
Allison E. Girasole
Neuroscience Graduate Program, UCSF, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA
Andrew J. Flores
Department of Neurosciences, UCSD, La Jolla, CA 92093, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
Emily L. Twedell
Neuroscience Graduate Program, UCSF, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
Matthew M. McGregor
Neuroscience Graduate Program, UCSF, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
Rea Brakaj
Department of Neurology, UCSF, San Francisco, CA 94158, USA
Ronald F. Paletzki
Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD 20892, USA
Thomas S. Hnasko
Department of Neurosciences, UCSD, La Jolla, CA 92093, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA 92161, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA
Charles R. Gerfen
Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, MD 20892, USA
Alexandra B. Nelson
Neuroscience Graduate Program, UCSF, San Francisco, CA 94158, USA; Kavli Institute for Fundamental Neuroscience, UCSF, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, UCSF, San Francisco, CA 94158, USA; Department of Neurology, UCSF, San Francisco, CA 94158, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA; Corresponding author
Summary: The striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions. However, the precise mechanisms underlying this process remain unclear. One way to study action selection is to understand how it breaks down in pathological states. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson’s 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. We found this differential activation of TRAPed dMSNs is likely to be driven by higher dopamine receptor expression, dopamine-dependent excitability, and excitatory input from the motor cortex and thalamus. Together, these findings suggest how the intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.
