Breathing dysfunction as a result of prodromal Parkinson's disease pathology in the locus coeruleus

Breathing is a resilient behavior, yet respiratory dysfunction occurs in many neurodegenerative diseases, including Parkinson’s Disease (PD). While the exact mechanisms underlying PD pathology are not completely understood, the disease is classically characterized by aggregated alpha-synuclein (α-syn). Years prior to diagnosis, individuals with PD often experience various non-motor symptoms, including respiratory dysfunction. Changes in respiratory output potentially correlates with pathology and cell death in brain regions afflicted early in the disease progression, such as the Locus Coeruleus (LC). The overarching goal of this project is to investigate the impact of locally induced α-syn pathology in the LC on the intrinsic properties of LC neurons and the subsequent impact on the control of breathing. To study prodromal PD symptoms and progression as they relate to LC function, we injected α-syn pre-formed fibrils (PFF) bilaterally into the LC region of C57BL/6J mice. At 1-week, 1-month, and 3-months post-injection, mice were assessed for changes in breathing function. We performed breathing measurements in a whole body plethysmograph and assessed respiratory rate and variability in normal room air, hypercapnia and hypoxia. Following this, we used immunohistochemistry to assess cellular pathology and neuronal death. To begin to elucidate the cellular substrates of breathing dysfunction, we used whole-cell patch clamp recordings to measure intrinsic LC neuron properties, such as excitability, firing rate, afterhyperpolarization, and action potential characteristics. At each time point assessed, PFF-injected mice exhibit significant increases in baseline respiratory rate, indicating dysfunction in LC-based respiratory circuitry. Whole-cell patch clamp recordings indicate that α-syn pathology-induced changes in LC excitability may be one of the contributors to this breathing phenotype. Mangurian-Fixel-McKnight Collaboration for Pilot Studies in Lewy Body Dementia McKnight Brain Institute Accelerator Award 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.