Network Dysfunction Precedes Neurodegeneration in a dox-Regulatable TDP-43 Mouse Model of ALS-FTD

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neuronal hyperexcitability is a key feature of amyotrophic lateral sclerosis (ALS).
• TDP-43 protein aggregates are the primary pathology in most ALS and frontotemporal lobar degeneration cases.
• The link between TDP-43 pathology and neuronal hyperexcitability remains incompletely understood.

Purpose of the Study:

• To investigate TDP-43-mediated network excitability changes in a relevant disease model.
• To determine if targeting neuronal hyperexcitability can prevent neurodegeneration in TDP-43 proteinopathies.

Main Methods:

• In vivo electroencephalography (EEG) and ex vivo hippocampal slice electrophysiology in rNLS8 mice expressing human TDP-43 with a defective nuclear localization signal (hTDP-43ΔNLS).
• Assessment of seizures, cortical EEG patterns, hippocampal circuit hyperexcitability, and AMPA subunit expression.
• Intervention with inhibitory DREADDs (hM4Di) in the hippocampus and systemic administration of anti-seizure medications (valproic acid, levetiracetam).

Main Results:

• Seizures occurred in approximately 64% of rNLS8 mice post-transgene induction.
• Longitudinal EEG changes and circuit hyperexcitability preceded neurodegeneration in vulnerable hippocampal subfields.
• Hippocampal DREADD-mediated hyperexcitability suppression improved anxiety-like behavior but did not reduce neurodegeneration.
• Systemic anti-seizure medications failed to improve behavior or prevent neurodegeneration.

Conclusions:

• TDP-43 pathology induces neuronal hyperexcitability and seizures that precede neurodegeneration.
• While targeting hyperexcitability can ameliorate some behavioral deficits, it is insufficient to halt or slow neurodegeneration in this model.
• These findings highlight the complex relationship between TDP-43, hyperexcitability, and neurodegeneration, suggesting limited therapeutic potential for solely targeting hyperexcitability.