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 (FTD), amyotrophic lateral sclerosis (ALS), 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 Tdp-43F/F mice, compared with that of 5xFAD mice, a well-established AD mouse model with ß-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. Overall design: TDP-43 loss-of-function in the medial prefrontal cortex (mPFC) was investigeted using a conditional knockout mouse model Tdp-43 F/F with focally injected AAV viruses expressing either Cre recombinase or GCaMP6f control, alongside 5xFAD mice as AD controls. Short-term (2 months) and long-term (6 months) knockout cohorts, with corresponding age-matched controls, were analyzed. Freshly dissected mPFC tissues were pooled and subjected to single-nucleus RNA sequencing (10x Genomics 3' platform).