Aberrant neural activity in prefrontal pyramidal neurons lacking TDP-43 precedes neuron loss. (August 2022)

• Record Type: Journal Article
• Authors: Liang, Bo; Thapa, Rashmi; Zhang, Gracie; Moffitt, Casey; Zhang, Yan; Zhang, Lifeng; Johnston, Amanda; Ruby, Hyrum P.; Barbera, Giovanni; Wong, Philip C.; Zhang, Zhaojie; Chen, Rong; Lin, Da-Ting; Li, Yun
• Is Part Of: Progress in neurobiology. Volume 215(2022)
• Publication Date: 2022-08
• Subjects: TDP-43 TAR DNA binding protein 43 kDa, or TARDBP-43 -- ALS amyotrophic lateral sclerosis -- FTD frontotemporal dementia -- AD Alzheimer's disease -- hnRNPs heterogeneous nuclear ribonucleoproteins -- Miniscope miniature fluorescence microscope -- PFC prefrontal cortex -- ACSF artificial cerebrospinal fluid -- GFAP glial fibrillary acidic protein -- AAV adeno-associated virus -- GRIN lens gradient index lens -- CTRL control -- KO knockout -- AUC/s area under curve per second -- TMS transcranial magnetic stimulation -- iPSC induced pluripotent stem cell -- SOD1 superoxide dismutase 1 -- FUS fused-in-sarcoma; Neurodegenerative disorders -- In vivo calcium imaging -- Aberrant neural activity -- Hyperactivity -- Hypoactivity; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2022.102297
• Languages: English
• ISSNs: 0301-0082

Abstract

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. Highlight: Loss of TDP-43 in PFC pyramidal neurons elicits aberrant calcium activity. Short-term loss of TDP-43 triggers hyperactivity in pyramidal neurons of the PFC. Rapid activity declines following the initial hyperactivity in pyramidal neurons lacking TDP-43 before neuron loss.