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Aberrant neural activity in prefrontal pyramidal neurons lacking TDP-43 precedes neuron loss

Aberrant neural activity in prefrontal pyramidal neurons lacking TDP-43 precedes neuron loss

Authors :
Bo Liang
Rashmi Thapa
Gracie Zhang
Casey Moffitt
Yan Zhang
Lifeng Zhang
Amanda Johnston
Hyrum P. Ruby
Giovanni Barbera
Philip C. Wong
Zhaojie Zhang
Rong Chen
Da-Ting Lin
Yun Li
Source :
Progress in neurobiology. 215
Publication Year :
2022

Abstract

Mislocalization of TAR DNA binding protein 43 kDa (TARDBP, or TDP-43) is a principal pathological hallmark identified in cases of neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). As an RNA binding protein, TDP-43 serves in the nuclear compartment to repress non-conserved cryptic exons to ensure the normal transcriptome. Multiple lines of evidence from animal models and human studies support the view that loss of TDP-43 leads to neuron loss, independent of its cytosolic aggregation. However, the underlying pathogenic pathways driven by the loss-of-function mechanism are still poorly defined. We employed a genetic approach to determine the impact of TDP-43 loss in pyramidal neurons of the prefrontal cortex (PFC). Using a custom-built miniscope imaging system, we performed repetitive in vivo calcium imaging from freely behaving mice for up to 7 months. By comparing calcium activity in PFC pyramidal neurons between TDP-43 depleted and TDP-43 intact mice, we demonstrated remarkably increased numbers of pyramidal neurons exhibiting hyperactive calcium activity after short-term TDP-43 depletion, followed by rapid activity declines prior to neuron loss. Our results suggest aberrant neural activity driven by loss of TDP-43 as the pathogenic pathway at early stage in ALS and FTD.

Details

ISSN :
18735118
Volume :
215
Database :
OpenAIRE
Journal :
Progress in neurobiology
Accession number :
edsair.doi.dedup.....2ae5ff34dfeb852e416c0ece624c67d9