Astrocyte Activation in the Substantia Nigra pars compacta Occurs Prior to Neurodegeneration and Appearance of Motor Deficits in a Rodent Model of Environmental Parkinsonism

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, characterized by the loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNpc) and the accumulation of α-synuclein aggregates (Lewy bodies) in the surviving neurons. These cellular hallmarks result in motor impairments (e.g. bradykinesia, tremor), loss of involuntary movement, and cognitive changes at the clinical level. There are also common non-motor symptoms which include olfactory deficits and gastrointestinal dysfunctions that decrease the patient’s quality of life, and precede the onset of motor symptoms. Previous work from our lab has described a novel environmental model of parkinsonism in rats that results from oral administration of subthreshold doses of paraquat (P) and lectin (L). This “bottom-up” (i.e., gut-brain) model results in synucleinopathy that is transported from the gut to the brainstem via the vagus nerve, and then to the SNpc where it induces neuronal loss and motor deficits. Astrocytes are important for neuronal survival but reactive astrogliosis may also promote neurodegeneration. The aim of this study was to assess astrocyte involvement in the SNpc during development of parkinsonism in our environmental rodent model. Male Sprague-Dawley rats (150g) were gavaged with P+L (1.5mg/kg and 0.75mg/kg, respectively, in 10% sucrose; N=10) or vehicle (10% sucrose; N=10) for 7 days. Rats were perfuse-fixed at 1, 2 and 3 weeks post-gavage, after which the brains were removed, post-fixed, and midbrain sections sliced at 50µm thickness and processed for immunohistochemical localization of glial fibrillary protein (GFAP) and tyrosine hydroxylase (TH) immunoreactivity (-IR). Z-stacked confocal microscopic images throughout the depth of the SNpc showed an increased intensity of GFAP-IR within the SNpc of the P+L (mean pixel density/mm 2 = 31.1 ± 3.065) compared to control group (mean = 8.69 ± 1.584, p <0.001). Slices were also stained for α-synuclein aggregates within TH-IR SNpc neurons. Misfolded a-synuclein was not observed within control TH-IR neurons and, although not reaching significance, there was an increasing trend for α-synuclein aggregates in P+L SNpc TH-IR neurons. These data suggest that astrocyte reactivity may be involved in the early stages of SNpc degeneration in this environmental model of parkinsonism. Given the potential dual neuroprotective and/or neurotoxic role of astrocytes, assessing the role of reactive astrogliosis, and its temporal pattern, would be important to uncovering the mechanistic basis of their involvement in neurodegeneration, as well as potential therapeutic targets for intervention. NIH DK124098 and DOD W81XWH2110915 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.