Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS
Abstract
Hyperexcitability of motor neurons and spinal cord motor circuitry has been widely reported in the early stages of Amyotrophic Lateral Sclerosis (ALS). Changes in the relative amount of excitatory to inhibitory inputs onto a neuron (E:I synaptic ratio), possibly through a developmental shift in synapse formation in favour of excitatory transmission, could underlie pathological hyperexcitability. Given that astrocytes play a major role in early synaptogenesis and are implicated in ALS pathogenesis, their potential contribution to disease mechanisms involving synaptic imbalances and subsequent hyperexcitability is also of great interest. In order to assess E:I ratios in ALS, we utilised a novel primary spinal neuron / astrocyte co-culture system, derived from neonatal mice, in which synapses are formed in vitro. Using multiple ALS mouse models we found that no combination of astrocyte or neuron genotype produced alterations in E:I synaptic ratios assessed using pre- and post-synaptic anatomical markers. Similarly, we observed that ephrin-B1, a major contact-dependent astrocytic synaptogenic protein, was not differentially expressed by ALS primary astrocytes. Further to this, analysis of E:I ratios across the entire grey matter of the lumbar spinal cord in young (post-natal day 16–19) ALS mice revealed no differences versus controls. Finally, analysis in co-cultures of human iPSC-derived motor neurons and astrocytes harbouring the pathogenic C9orf72 hexanucleotide repeat expansion showed no evidence of a bias toward excitatory versus inhibitory synapse formation. We therefore conclude, utilising multiple ALS models, that we do not observe significant changes in the relative abundance of excitatory versus inhibitory synapses as would be expected if imbalances in synaptic inputs contribute to early hyperexcitability.
Citation
Bonthron , C , Burley , S , Broadhead , M J , Metodieva , V V , Grant , S , Chandran , S & Miles , G B 2024 , ' Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS ' , PLoS ONE , vol. 19 , no. 8 , e0306423 . https://doi.org/10.1371/journal.pone.0306423
Publication
PLoS ONE
Status
Peer reviewed
ISSN
1932-6203Type
Journal article
Description
Funding: Motor Neurone Disease (MND) Association UK (authors: M.J.B., G.B.M., S.C.; grant number: Miles/Apr18/863-791; URL: https://www.mndassociation.org/), the SPRINT MND/MS PhD Programme (authors: C.B.; URL: https://www. edinburghneuroscience.ed.ac.uk/edneurophd/ sprint-mndms-phd-programme), Wellcome Trust (authors: S.G.N.G; grant number: Technology Development Grant 202932; URL:https://wellcome.org/), the European Union Seventh Framework Programme (authors: S.G.N.G.; grant numbers: HEALTH- F2-2009-241498 and 720270; URL: https://ec.europa.eu/commission/presscorner/ detail/hu/MEMO_16_146) and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programe (authors: S.G.N.G.; grant number: 695568, URL: https://erc.europa.eu/homepage).Collections
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