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University of Florida Health University of Florida
Norman Fixel Institute for
Neurological Diseases
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principal investigator

study rationale

Frontotemporal dementia (FTD), caused by progressive brain degeneration, affects motor and language functions, often linked to GRN gene mutations. GRN mutations account for up to 20% of familial FTD cases, leading to reduced progranulin levels and associated neurodegenerative changes. Understanding the impact of GRN mutations on basal ganglia function could reveal mechanisms underlying motor symptoms and aphasia, which remain poorly understood. This study utilizes GRN knock-in (KI) mice to explore these effects, aiming to identify potential therapeutic targets​.

hypothesis

GRN KI mice exhibit motor and communication deficits due to molecular, anatomical, and functional changes in basal ganglia neurons, specifically dopaminergic (DAergic) neurons and cholinergic interneurons (ChIs). These deficits result from the heterozygous loss of progranulin function​.

study design

  • Aim 1: Characterize motor and non-motor behaviors in GRN KI mice using tests such as the accelerated rotarod, beam-walking, and ultrasound vocalization.
  • Aim 2: Analyze the electrophysiological properties of basal ganglia neurons, particularly DAergic neurons, to determine their role in motor and communication deficits​.

impact

By elucidating the contribution of basal ganglia dysfunction to GRN-FTD symptoms, this study may identify pathways for targeted interventions, improving quality of life for patients with motor and language impairments associated with GRN-FTD.

next steps for development

Data from this project will form the basis for R-type grant applications to further investigate the mechanisms and therapeutic options for GRN-FTD. This research aligns with broader efforts to understand neurodegenerative diseases and advance treatment strategies​.

Additional information

The total project budget of $24,391 includes support for personnel, animal care, and materials. Experiments will use GRN KI mice and advanced behavioral and electrophysiological techniques to assess motor and non-motor deficits.

collaboration

The multidisciplinary team includes:

  • Dr. Yuqing Li: Principal Investigator with expertise in movement disorders and mouse models.
  • Dr. Hong Xing: Co-investigator specializing in electrophysiology and dopamine signaling.
  • Pallavi Girdhar: Graduate student experienced in behavioral analysis and AI-based pattern recognition for vocalization studies​