Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting nearly one million people in the United States. Recent studies have indicated that idiopathic PD may originate in the gastrointestinal (GI) tract and then spread, via the efferent vagus nerve, to the dorsal motor nucleus of the vagus (DMV) neurons within the brainstem and then to the substantia nigra pars compacta (SNpc), via a monosynaptic dopaminergic nigro-vagal pathway. Preganglionic parasympathetic DMV neurons regulate GI functions and involvement of these neurons in PD pathogenesis may explain the prodromal GI symptoms, such as gastroparesis and constipation, that are experienced by up to 80% of PD patients. DMV neurons are under tonic GABAergic inhibition. The inhibitory role of GABA depends on the neuronal chloride gradient, which is regulated by the chloride co-transporter KCC2 in mature neurons. The purpose of this study was to test the hypothesis that downregulation of KCC2 induces DMV maladaptive plasticity that contributes to disease pathogenesis in a rodent model of parkinsonism. The current study used a rodent model of environmental parkinsonism, in which oral gavage of rats with subthreshold doses of the herbicide paraquat (P), combined with a dietary glycoprotein lectin (L), has been shown to induce levodopa-responsive parkinsonism accompanied by delayed gastric emptying. This P+L model also triggers the formation of pathological α-synuclein (α-syn) in the GI tract, as well as in the DMV and SNpc, causing significant degeneration (~50%) of dopaminergic neurons in the SNpc. In male Sprague Dawley rats, cell-attached (n = 6-10 neurons for each time point) and perforated patch clamp recordings (n= 4-6 neurons per group) were made from DMV neurons to assess the maladaptive DMV neuroplasticity associated with alterations in GABAergic inhibition asswociated with changes in the neuronal chloride gradient. One week after P+L treatment, DMV neurons showed a positive shift in chloride reversal potential (-59.4 ± 4.1pA vs. -46.0 ± 1.6pA, p = 0.0082). This positive shift in chloride reversal potential was also associated with a decreased inhibitory role of GABA, as assessed by the reduced ability of the GABAA receptor antagonist, bicuculline, to increase action potential firing rate (Week 1 = 227.2% ± 54.2% of baseline, Week 2 = 119.1 ± 7.5% of baseline, Week 3 =126.0 ± 21.5% of baseline, Week 4 = 90.7 ± 10.2% of baseline, one-way ANOVA p = 0.0004). These studies suggest that, in an environmental model of parkinsonism, DMV maladaptive plasticity is associated with altered tonic GABAergic inhibition subsequent to dysregulation of the neuronal chloride gradient. Since the excitability of DMV neurons is dependent upon tonic GABAergic inhibition, these changes may underlie the dysregulated gastric functions, including delayed gastric emptying, observed in this preclinical rodent model, as well as in PD patients. Investigating early prodromal pathologies may provide valuable insights into disease etiology as well as identify translationally relevant targets for novel therapeutic intervention strategies. This abstract was presented at the American Physiology Summit 2026 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.
Ozkaya et al. (Fri,) studied this question.