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


Handley, EE and Pitman, KA and Dawkins, E and Young, KM and Clark, RM and Jiang, TC and Turner, BJ and Dickson, TC and Blizzard, CA, Synapse dysfunction of layer V pyramidal neurons precedes neurodegeneration in a mouse model of TDP-43 proteinopathies, Cerebral Cortex, 27, (7) pp. 3630-3647. ISSN 1047-3211 (2016) [Refereed Article]

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Copyright 2016 The Authors. Published by Oxford University Press

DOI: doi:10.1093/cercor/bhw185


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.

Item Details

Item Type:Refereed Article
Keywords:amyotrophic lateral sclerosis, dendrite spine, frontotemporal dementia, synapse, Tar-DNA binding protein 43
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Handley, EE (Miss Emily Handley)
UTAS Author:Pitman, KA (Dr Kimberley Pitman)
UTAS Author:Dawkins, E (Dr Edgar Dawkins)
UTAS Author:Young, KM (Professor Kaylene Young)
UTAS Author:Clark, RM (Dr Rosie Clark)
UTAS Author:Jiang, TC (Miss Tongcui Jiang)
UTAS Author:Dickson, TC (Professor Tracey Dickson)
UTAS Author:Blizzard, CA (Dr Catherine Blizzard)
ID Code:110832
Year Published:2016
Web of Science® Times Cited:42
Deposited By:Wicking Dementia Research and Education Centre
Deposited On:2016-08-17
Last Modified:2017-11-23

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