Mechanisms of Cortical Excitability Changes in Frontotemporal Degeneration Onset
Abstract
Head injuries, including combat-related trauma like TBI, increase lifetime risk of acquired dementias, including Frontotemporal Degeneration (FTD). A major pathological mechanism of dementias like FTD is misfolding and aggregation of Tau isoforms. But there is not yet an effective treatment targeting Tau aggregation that addresses clinical symptoms or slows disease progression. Early pathological changes include hyperexcitability and increased seizure incidence, which precede substantial Tau aggregation and FTD diagnosis. There is a significant knowledge gap about how changes in circuits lead to hyperexcitability. Understanding the pathogenesis in the cortical circuit might help identify potential therapeutic targets to treat or slow the progression of FTD. We hypothesize that pre-tangle mutant Tau induces circuit changes, resulting in weakened inhibition or increased neuronal excitability in specific circuit components. Our specific aims test this hypothesis. To model FTD, we will express a mutant Tau isoform (P301L) in a mouse model to dissect cell-type specific circuitry. This approach allows use of transgenic lines to fluorescently label and manipulate targeted neuron populations, allowing the study of mutant Tau effects in specific connections. Use of viral vectors also allows the study of direct effects on neuronal circuits in defined cortical areas, eliminating the need to control for compensatory mechanisms as intransgenic mutant Tau mice and enabling control of the onset time of mutant Tau expression. Stereotaxic injections of viral vectors expressing mutant Tau will be made in the primary motor cortex (M1), a brain region whose general circuit connectivity is understood. We will measure changes in inhibitory connection strength as well as intrinsic excitability by targeted whole-cell recordings in mouse brain slice.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2022
- Accession Number
- AD1172663
Entities
People
- Bryan M Hooks
- Roman Goz
Organizations
- University of Pittsburgh