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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number102297
JournalProgress in Neurobiology
Volume215
DOIs
StatePublished - Aug 2022

Keywords

  • Aberrant neural activity
  • Hyperactivity
  • Hypoactivity
  • In vivo calcium imaging
  • Neurodegenerative disorders

ASJC Scopus subject areas

  • General Neuroscience

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