Synaptopathy in the TDP43ΔNLS Mouse Model of Sporadic Amyotrophic Lateral Sclerosis

Sporadic cases of Amyotrophic Lateral Sclerosis (sALS) represent the most common form of motor neuron disease. sALS is characterised by pathological cytoplasmic inclusions of TDP-43, so-called reactive astrocyte pathology, and motor neuron degeneration. Early-stage alterations in certain subpopulations of synapses between neurons are thought to be a key driver of the early pathological mechanisms of ALS. However, we do not have a clear understanding of which types of synapses are impacted in ALS. Identifying vulnerable synapses affected in sALS models may provide insights into the key sites of disease pathogenesis. In this study we have performed quantitative high-resolution microscopy to survey different synapse subtypes, including excitatory (glutamatergic), inhibitory (glycinergic) and modulatory (cholinergic C-Bouton) synapses, in the spinal cord of a mouse model of sALS showing inducible TDP-43 pathology (TDP43{Delta}NLS) restricted to neurons. We have identified changes in cholinergic synapses and a subpopulation of excitatory synapses. Mice display robust neuronal TDP-43 pathology and evidence of TDP-43 changes at cholinergic C-boutons. We also observe no evidence of astrocytic pathology nor changes in the fraction of synapses that are contacted by astrocytes, demonstrating that synapse pathology is driven by cell-autonomous (neuronal) mechanisms. Overall, our findings highlight the selective vulnerability of distinct synapse populations in ALS.