title: Cortical synaptic and dendritic spine abnormalities in a presymptomatic TDP-43 model of amyotrophic lateral sclerosis.
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-43Q331Kmutation. 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.
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fogarty
authors.affiliation: Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Klenowski
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Lee
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Joy R
authors.initials: JR
authors.lastname: Drieberg-Thompson
authors.affiliation: Translational Research Institute, Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Selena E
authors.initials: SE
authors.lastname: Bartlett
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.|Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|University of Queensland Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia.|Department of Neurology, Royal Brisbane &Women's Hospital, Brisbane, QLD, Australia.
authors.forename: Shyuan T
authors.initials: ST
authors.lastname: Ngo
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Massimo A
authors.initials: MA
authors.lastname: Hilliard
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Bellingham
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.|Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Noakes
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology*; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology*; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009044:Motor Cortex / Q000378:metabolism / Q000473:pathology*; D009410:Nerve Degeneration; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology*; D013569:Synapses / Q000378:metabolism / Q000473:pathology*; D009435:Synaptic Transmission
chemical_list: D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse