Single-nucleus RNA sequencing reveals GABAergic vulnerability and reactive gliosis driven by loss of TDP-43

TDP-43 is an RNA-binding protein important for RNA processing, whose loss of function is involved in multiple neurodegenerative disorders, including frontotemporal dementia, amyotrophic lateral sclerosis, and Alzheimer's disease (AD). We performed single-nucleus RNA-sequencing to study the convergent and divergent molecular signatures of short-term and long-term TDP-43 depletion in the medial prefrontal cortex (mPFC) using <i>Tdp-43</i> ^<i>F/F</i> mice, compared with that of 5xFAD mice, a well-established AD mouse model with β-amyloid plaque pathology. Our results demonstrated a significant loss of GABAergic neurons in the mPFC after short-term TDP-43 depletion. This was accompanied by a remarkable reactive gliosis in the mPFC. Our results revealed a strong GABAergic and glial involvement during early stages of TDP-43 loss of function, suggesting that the GABAergic system is vulnerable to TDP-43 pathology and could be considered a potential target for developing therapeutic strategies and biomarkers for early detection in TDP-43 linked AD-related dementia.