Mechanisms of Cortical Excitability Changes in Frontotemporal Degeneration Onset
Abstract
FY20 PRMRP Topic Area: Frontotemporal Dementia Brain injuries such as mild traumatic brain injury (TBI) increase the lifetime risk for dementias, including Frontotemporal Degeneration (FTD). These disorders lack effective medical treatments. FTD research concentrates on molecular mechanisms of toxic protein aggregation and spread of Tau protein, which forms neurofibrillary tangles in late stages of FTD. However, increased excitability, including susceptibility to epileptic seizures, occurs at much earlier stages. Uncovering early changes in neural circuitry causing hyperexcitability by using methods for cell-type specific circuit mapping may provide better diagnostic markers and identify specific cellular targets for treatment. Hyperexcitability in neuronal circuits may result from reduced inhibition due to weakening of inhibitory synapses or degeneration of inhibitory neurons. Stronger excitatory connections or changes in intrinsic excitability of specific cells might also cause hyperexcitability. Our proposal tests the hypothesis that Tau-induced changes will cause hyperexcitability by changing connectivity of specific inhibitory cell types. By targeting recordings to specific cortical neurons using transgenic mouse models labeling to label specific inhibitory and excitatory cells, this proposal will establish the specific circuit location of early changes causing hyperexcitability. Expression of mutant Tau by viral injection (AAV) will be used to induce a model of FTD-like changes in mouse frontal cortex. State-of-the-art optogenetic tools (light sensitive channelrhodopsin molecules expressed in live cells) will be used to excite specific connections for circuit mapping. Recordings will be targeted to genetically defined subsets of inhibitory or excitatory neurons, allowing reliable identification of the same cell types (circuit nodes) across experiments. Changes in excitability and connectivity will be quantified and compared for each cell type in mutant Tau-expressing and neighboring neurons. The circuit location where changes in connectivity and excitability occur are then targets for therapeutic intervention to slow FTD progression.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110250
Entities
People
- Roman Goz
Organizations
- United States Army
- University of Pittsburgh