Abstract
Dyskinesia associated with chronic levodopa treatment in Parkinson’s disease is associated with maladaptive striatal plasticity. The objective of this study was to examine whether macroscale structural changes, as captured by magnetic resonance imaging (MRI) accompany this plasticity and to identify plausible cellular contributors in a rodent model of levodopa-induced dyskinesia. Adult male Sprague-Dawley rats were rendered hemi-parkinsonian by stereotaxic injection of 6-hydroxydopamine into the left medial forebrain bundle prior to chronic treatment with saline (control) or levodopa to induce abnormal involuntary movements (AIMs), reflective of dyskinesia. Perfusion-fixed brains underwent ex vivo structural MRI before sectioning and staining for cellular markers. Chronic treatment with levodopa induced significant AIMs (p < 0.0001 versus saline). The absolute volume of the ipsilateral, lesioned striatum was increased in levodopa-treated rats resulting in a significant difference in percentage volume change when compared to saline-treated rats (p < 0.01). Moreover, a significant positive correlation was found between this volume change and AIMs scores for individual levodopa-treated rats (r = 0.96; p < 0.01). The density of Iba1+ cells was increased within the lesioned versus intact striatum (p < 0.01) with no difference between treatment groups. Conversely, Iba1+ microglia soma size was significantly increased (p < 0.01) in the lesioned striatum of levodopa-treated but not saline-treated rats. Soma size was not, however, significantly correlated with either AIMs or MRI volume change. Although GFAP+ astrocytes were elevated in the lesioned versus intact striatum (p < 0.001), there was no difference between treatment groups. No statistically significant effects of either lesion or treatment on RECA1, a marker for blood vessels, were observed. Collectively, these data suggest chronic levodopa treatment in 6-hydroxydopamine lesioned rats is associated with increased striatal volume that correlates with the development of AIMs. The accompanying increase in number and size of microglia, however, cannot alone explain this volume expansion. Further multi-modal studies are warranted to establish the brain-wide effects of chronic levodopa treatment.
Highlights
Levodopa (L-DOPA) remains a first-line treatment for motor symptoms in many individuals affected by Parkinson’s disease (PD) (Schapira et al, 2009)
The main findings of this study are that chronic L-DOPA treatment of 6-OHDA lesioned rats is associated with an apparent increase in the volume of the ipsilateral, lesioned striatum, as measured from ex vivo MR images, leading to a leftward shift in striatal volume asymmetry index
While we found evidence for lesion-related increases in GFAP+ astrocyte immunoreactivity and Iba1+ microglia density, these again were unrelated to L-DOPA treatment under the current experimental conditions
Summary
Levodopa (L-DOPA) remains a first-line treatment for motor symptoms in many individuals affected by Parkinson’s disease (PD) (Schapira et al, 2009). Research efforts to unravel the neural correlates of LID in the clinic and in relevant animal models for LID are critical to address the gaps in our knowledge of LID pathogenesis In this context, regions of the basal ganglia that regulate motor function and are dysfunctional in PD have been explored extensively in both dyskinetic PD patients and rodent LID models using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET). L-DOPA treatment is associated with increased vascular perfusion (indexed by cerebral blood flow or [15O]-H2O PET) that is dissociated from metabolic changes (indexed by cerebral glucose utilization via [18F]fluorodeoxyglucose PET) in the basal ganglia, motor and prefrontal cortices (Hirano et al, 2008) Back translating these measures to rodent models for LID has resulted in similar observations (Ohlin et al, 2012; Lerner et al, 2016), paving the way to probing the underling physiological and cellular correlates of these functional changes. Evidence from such invasive studies strongly suggests that development of LID is associated with maladaptive synaptic plasticity in striatal medium spiny and cortical pyramidal neurons, with corresponding morphological changes such as increased dendritic spine density (Deutch et al, 2007; Zhang et al, 2013; Finlay et al, 2014; Nishijima et al, 2014; Suarez et al, 2014; Ueno et al, 2014, 2017)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
