title: Synapse Dysfunction of Layer V Pyramidal Neurons Precedes Neurodegeneration in a Mouse Model of TDP-43 Proteinopathies.
abstract: 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.
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Emily E
authors: EE
authors: Handley
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Kimberley A
authors: KA
authors: Pitman
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Edgar
authors: E
authors: Dawkins
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Kaylene M
authors: KM
authors: Young
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Rosemary M
authors: RM
authors: Clark
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Tongcui C
authors: TC
authors: Jiang
authors: Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3052, Australia.
authors: Bradley J
authors: BJ
authors: Turner
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Tracey C
authors: TC
authors: Dickson
authors: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
authors: Catherine A
authors: CA
authors: Blizzard
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000367:Age Factors; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics; D002540:Cerebral Cortex / Q000473:pathology*; D049229:Dendritic Spines / Q000473:pathology / Q000648:ultrastructure*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000209:etiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000473:pathology*; D013569:Synapses / Q000648:ultrastructure*; D057177:TDP-43 Proteinopathies / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018800:Thy-1 Antigens; C054562:yellow fluorescent protein, Bacteria
keywords: Dendrite spine; Tar-DNA binding protein 43; amyotrophic lateral sclerosis; frontotemporal dementia; synapse