Neuroanatomical and Microglial Alterations in the Striatum of Levodopa-Treated, Dyskinetic Hemi-Parkinsonian Rats

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 levodopatreated 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 levodopatreated 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

Histological Correlates of Neuroanatomical Changes in a Rat Model of Levodopa-Induced Dyskinesia Based on Voxel-Based Morphometry

“…In this study, compared with PD rats, LID rats showed a significant volume increase in the lesioned dorsolateral striatum. This is consistent with the findings of a recent structural MRI study in vitro (Fletcher et al, 2020), which reported an absolute volume expansion in the lesioned striatum of chronic L-DOPA-treated rats, compared with saline-treated rats. Moreover, this previous study reported a positive correlation between volume changes and AIMs scores, which suggested that microglia may be involved in this process.…”

“…This is consistent with previous reports of significant astrogliosis in the lesioned striatum (Bortolanza et al, 2015;Ramírez-García et al, 2015;Fonteles et al, 2020). Contrastingly, another study observed no related differences between rats treated with saline and L-DOPA (Fletcher et al, 2020), arguing against the contribution of astrogliosis to the volume expansion. This discrepancy could be attributed to the administration of higher L-DOPA dose (12 mg/kg, i.p.…”

“…Several studies using functional magnetic resonance imaging (fMRI) (Herz et al, 2016) and positron emission tomography (PET) (Rascol et al, 1998;Brooks et al, 2000) have reported that LID involves molecular changes, metabolism, and abnormal brain network connections in the cortex-striatumcortex loop. Electrophysiological and neuropathological studies have suggested that LID results from long-term adaptive brain plasticity (Belujon et al, 2010;Ohlin et al, 2011;Zheng et al, 2020), which could be attributed to neuroanatomical remodeling at the level of cells (Bortolanza et al, 2015;Mulas et al, 2016;Fletcher et al, 2020), spine and synapses (Zhang et al, 2013;Suarez et al, 2016;Fieblinger et al, 2018), or blood vessels (Lindgren et al, 2009;Ohlin et al, 2011;Booth et al, 2021). It remains unclear whether these cellular contributors cause macroscopic structural changes in the brain volume of LID.…”

“…Moreover, the precise cellular mechanisms underlying the neuroanatomical changes remains unclear due to the limited resolution in human imaging studies. Combining well-validated animal models of LID with advanced non-invasive and accessible structural MRI methods (Duty and Jenner, 2011;Fletcher et al, 2020) could overcome this limitation and allow direct integration of different research areas, accelerate the clinical translation of basic findings, and facilitate explanation of MRI phenomena in dyskinetic patients (Finlay et al, 2014).…”

Current Knowledge on the Background, Pathophysiology and Treatment of Levodopa-Induced Dyskinesia—Literature Review

“…The degree of asymmetry between sites in the size of the dorsal striatum components, putamen and caudate nucleus, at the onset of PD, was found to be a predictor of the development of LID, but also of the response to L-DOPA treatment [ 3 ]. The microscopic changes, although evident, did not appear to be directly related to striatal growth or the axial, limb and orolingual AIMs scores, measured together using established criteria of amplitude and severity [ 14 ].…”