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Sci Rep. 2016 Nov 29;6:37968. doi: 10.1038/srep37968.

Cortical synaptic and dendritic spine abnormalities in a presymptomatic TDP-43 model of amyotrophic lateral sclerosis.

Author information

1
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
2
Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.
3
Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
4
University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.
5
Department of Neurology, Royal Brisbane &Women's Hospital, Brisbane, QLD, Australia.

Abstract

Layer V pyramidal neurons (LVPNs) within the motor cortex integrate sensory cues and co-ordinate voluntary control of motor output. In amyotrophic lateral sclerosis (ALS) LVPNs and spinal motor neurons degenerate. The pathogenesis of neural degeneration is unknown in ALS; 10% of cases have a genetic cause, whereas 90% are sporadic, with most of the latter showing TDP-43 inclusions. Clinical and experimental evidence implicate excitotoxicity as a prime aetiological candidate. Using patch clamp and dye-filling techniques in brain slices, combined with high-resolution confocal microscopy, we report increased excitatory synaptic inputs and dendritic spine densities in early presymptomatic mice carrying a TDP-43Q331K mutation. These findings demonstrate substantive alterations in the motor cortex neural network, long before an overt degenerative phenotype has been reported. We conclude that increased excitatory neurotransmission is a common pathophysiology amongst differing genetic cases of ALS and may be of relevance to the 95% of sporadic ALS cases that exhibit TDP-43 inclusions.

PMID:
27897242
PMCID:
PMC5126629
DOI:
10.1038/srep37968
[Indexed for MEDLINE]
Free PMC Article

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