University Of Tasmania

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Synapse dysfunction of layer V pyramidal neurons precedes neurodegeneration in a mouse model of TDP-43 proteinopathies

journal contribution
posted on 2023-05-18, 21:37 authored by Handley, EE, Kimberley PitmanKimberley Pitman, Dawkins, E, Kaylene YoungKaylene Young, Rosemary ClarkRosemary Clark, Jiang, TC, Turner, BJ, Tracey DicksonTracey Dickson, Catherine BlizzardCatherine Blizzard
TDP-43 is a major protein component of pathological neuronal inclusions that are present in frontotemporal dementia and amyotrophic lateral sclerosis. We report that TDP-43 plays an important role in dendritic spine formation in the cortex. The density of spines on YFP+ pyramidal neurons in both the motor and somatosensory cortex of Thy1-YFP mice, increased significantly from postnatal day 30 (P30), to peak at P60, before being pruned by P90. By comparison, dendritic spine density was significantly reduced in the motor cortex of Thy1-YFP::TDP-43A315T transgenic mice prior to symptom onset (P60), and in the motor and somatosensory cortex at symptom onset (P90). Morphological spine-type analysis revealed that there was a significant impairment in the development of basal mushroom spines in the motor cortex of Thy1-YFP::TDP-43A315T mice compared to Thy1-YFP control. Furthermore, reductions in spine density corresponded to mislocalisation of TDP-43 immunoreactivity and lowered efficacy of synaptic transmission as determined by electrophysiology at P60. We conclude that mutated TDP-43 has a significant pathological effect at the dendritic spine that is associated with attenuated neural transmission.


Publication title

Cerebral Cortex










Menzies Institute for Medical Research


Oxford Univ Press Inc

Place of publication

Journals Dept, 2001 Evans Rd, Cary, USA, Nc, 27513

Rights statement

Copyright 2016 The Authors. Published by Oxford University Press

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Socio-economic Objectives

Clinical health not elsewhere classified