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.

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

“…Although our classification system is limited compared to more recent molecular (notably ctip2 expression ref. 64) and functional approaches, (see refs 35, 36, 37 for reviews), our observations of increased spine density in TDP-43 Q331K LVPNs compared to WT, when accounting for neuronal type (tufted and slender) ties into a broadening of ALS clinical features to include callosal and further cerebral involvement656667 and is in line with widespread (regional and layer) cortical changes in rodent models2150.…”

“…In line with clinical studies9101112424648, increased excitatory neurotransmission may be a key pathogenic mechanism that has been recapitulated functionally in SOD1 G93A rodent models1617. Although impaired inhibitory neurotransmission and dendritic arbor regression has been previously reported in TDP-43 A315T mice, these changes were not accompanied by increased excitatory synaptic transmission or increased dendritic spine density45; however, subsequent investigations, without reporting inhibitory synaptic transmission, have reported decreased excitatory synaptic transmission by P6050. Our electrophysiological measurements of spontaneous EPSCs and IPSCs consist of a combination of miniature (TTX insensitive) synaptic currents and synaptic currents caused by presynaptic neuron firing (TTX sensitive) within our in vitro cortical slice preparations.…”

“…We propose that the substantial delay in neuronal loss in the cortex of P26-35 TDP-43 Q311K mice (compared to the SOD1 G93A model) is indicative of a much earlier presymptomatic stage in this model, when compared to P26-35 SOD1 G93A mice, which have already entered a period of dendritic and dendritic spine degeneration1621. Indeed a recent study in TDP-43 A315T mice showed decreased spine density by P6050, substantially later than the earliest findings in the SOD1 model1621. A similar progression pattern, with neurons exhibiting increased spine density compared to controls, followed by a lower spine density compared to controls at late stages of disease, has been reported for Huntington’s disease patients5556.…”

TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss

“…Previous studies indicate a causal role for TDP-43 neuronal pathology in the pathogenesis of neurodegeneration and synaptic loss using animal models of disease. These studies suggest, in fact, a cell-autonomous TDP-43 neurotoxicity (Igaz et al., 2011, Xu et al., 2011, Diaper et al., 2013, Yang et al., 2014, Medina et al., 2014, Handley et al., 2016). …”

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

“…In particular, the transgenic mice exhibited impaired learning and memory, progressive motor dysfunction, and hippocampal atrophy accompanied by increased levels of gliosis [342,343]. Transgenic mice expressing TDP43 A315T showed age-dependent reduction in the development of basal mushroom spines that lead to lower efficacy of synaptic transmission within the motor cortex as determined by electrophysiology [344]. Interestingly, opposite results were observed after overexpressing the TDP43 Q331K mutation, which lead to increased excitatory synaptic inputs and dendritic spine densities [345].…”