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-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.

Marked bias towards spontaneous synaptic inhibition distinguishes non-adapting from adapting layer 5 pyramidal neurons in the barrel cortex

“…The difference in IPSC frequency that we observed is maintained during action potential blockade, matching results from genetically labeled neurons in L5 of the primary motor cortex of mice and from neurons classified by the presence or absence of burst firing in L5 of the primary auditory cortex of rats 64 , 65 . A possible cause of the elevated mIPSC frequency in non-adapting neurons is a higher number of GABAergic synapses on these cells, which have been shown to have wider dendritic tufts with a dendritic area significantly larger than that of thin-tufted neurons 1 , 10 , 66 , 67 , consistent with our results (Fig. 1i,j ).…”

Modulation of human corticospinal excitability by paired associative stimulation in patients with amyotrophic lateral sclerosis and effects of Riluzole

“…Other authors have instead hypothesized a dying-forward model, with a reduction in SICI and an increase in ICF preceding lower motor neuron impairment [56]. Moreover, Fogarty observed an increase in dendritic spine density in the pyramidal motor neurons of ALS patients, thereby explaining the increased excitatory neurotransmission [57]. In our small sample of monomelic onset patients, the unaffected side may be considered as a pre-symptomatic model of disease; indeed, the…”

Occasional essay: Upper motor neuron syndrome in amyotrophic lateral sclerosis

“…Abnormalities in Betz cells and pyramidal cells of the primary motor cortex in sporadic and familial ALS, and in ALS-FTLD, include fragmentation, vacuolation, atrophy of apical dendrites, loss of spines, apical dendrite retraction and loss of postsynaptic densities 80–83. Studies in animal models suggest that dendritic pathology is an early, indeed presymptomatic feature of ALS84–86 and that TDP-43 cytoplasmic mislocalisation is associated with a reduction in dendritic spine density 8687.…”