Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.
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 syna...
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0306423&type=printable |
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| author | Calum Bonthron Sarah Burley Matthew J Broadhead Vanya Metodieva Seth G N Grant Siddharthan Chandran Gareth B Miles |
| author_facet | Calum Bonthron Sarah Burley Matthew J Broadhead Vanya Metodieva Seth G N Grant Siddharthan Chandran Gareth B Miles |
| author_sort | Calum Bonthron |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-5eddee5f793c4dbe8f33a152d267b332 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-5eddee5f793c4dbe8f33a152d267b3322025-08-20T03:25:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032024-01-01198e030642310.1371/journal.pone.0306423Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.Calum BonthronSarah BurleyMatthew J BroadheadVanya MetodievaSeth G N GrantSiddharthan ChandranGareth B MilesHyperexcitability 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0306423&type=printable |
| spellingShingle | Calum Bonthron Sarah Burley Matthew J Broadhead Vanya Metodieva Seth G N Grant Siddharthan Chandran Gareth B Miles Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS. PLoS ONE |
| title | Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS. |
| title_full | Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS. |
| title_fullStr | Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS. |
| title_full_unstemmed | Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS. |
| title_short | Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS. |
| title_sort | excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of als |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0306423&type=printable |
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