Impact of Pathological Tau on Circuit Function in Phenotypic Mouse Models of Progressive Supranuclear Palsy

/Abstract Progressive supranuclear palsy (PSP) is a rare neurodegenerative motor disorder affecting approximately 20,000 people in the U.S. Clinical hallmarks of PSP are early loss of balance and falls, together with impairment in saccadic eye movements. Additional features often mimic Parkinson’s disease (PD), but PD treatments provide little to no therapeutic benefits in PSP. Histopathologically, PSP is characterized by the presence of insoluble aggregates of the microtubule-associated protein, Tau. While disease-causing mutations to the Tau- encoding MAPT gene have been described, the majority of PSP cases are idiopathic. Postmortem analysis of PSP patient brains show Tau pathology in several motor control regions, such as the basal ganglia (e.g. striatum, subthalamic nucleus, substantia nigra) and midbrain eye movement nuclei. Recent findings indicate basal ganglia output nuclei, such as the substantia nigra, are among the first sites of neuronal pathology. Tau pathology in these regions may lead to physiological dysfunction of motor circuits, in turn driving motor symptoms seen in PSP. To test this hypothesis, we recently repurposed a previously described Tau transgenic mouse and determined that Tau pathology in the mice was sufficient to mimic two key clinical aspects of PSP: gait and eye movement abnormalities. Using custom-built gait and eye movement recording systems, we observed that Tau hP301S mice had impaired coordination and vertical eye movements. Furthermore, we find these phenotypes correlate with pathology in many PSP-associated motor control regions, such as the substantia nigra and mesencephalic locomotor region. We also find that expressing mutant Tau specifically in the substantia nigra is sufficient to mimic these same abnormal phenotypes. In this proposal, I will use these two new mouse models to test my central hypothesis that Tau pathology leads to behavioral deficits via physiological abnormalities in midbrain motor regions, the substantia nigra pars reticulata and the mesencephalic locomotor region. I will use a combination of in vivo electrophysiology, ex vivo patch-clamp recordings, and quantitative measures of eye movement and gait to identify these links between pathology, physiology, and behavior. Understanding these mechanisms may help focus future work on both the underlying mechanism of PSP and identify new treatment strategies. The experiments proposed in this study expands upon my prior ex vivo slice electrophysiology training and adds training in in vivo electrophysiology and complex behaviors. In addition, I have assembled an expert mentoring team to provide guidance in my career development with the goal of launching a career as a successful independent investigator at a biomedical research institution. Project Number: 1K99NS142566-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Rose Creed | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $136,620 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 ICN-T (94)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11299158