© The Author(s), 2022.Background: Synaptic and neuronal loss contribute to network dysfunction and disability in multiple sclerosis (MS). However, it is unknown whether excitatory or inhibitory synapses and neurons are more vulnerable and how their losses impact network functioning. Objective: To quantify excitatory and inhibitory synapses and neurons and to investigate how synaptic loss affects network functioning through computational modeling. Methods: Using immunofluorescent staining and confocal microscopy, densities of glutamatergic and GABAergic synapses and neurons were compared between post-mortem MS and non-neurological control cases. Then, a corticothalamic biophysical model was employed to study how MS-induced excitatory and inhibitory synaptic loss affect network functioning. Results: In layer VI of normal-appearing MS cortex, excitatory and inhibitory synaptic densities were significantly lower than controls (reductions up to 14.9%), but demyelinated cortex showed larger losses of inhibitory synapses (29%). In our computational model, reducing inhibitory synapses impacted the network most, leading to a disinhibitory increase in neuronal activity and connectivity. Conclusion: In MS, excitatory and inhibitory synaptic losses were observed, predominantly for inhibitory synapses in demyelinated cortex. Inhibitory synaptic loss affected network functioning most, leading to increased neuronal activity and connectivity. As network disinhibition relates to cognitive impairment, inhibitory synaptic loss seems particularly relevant in MS.
| Original language | English |
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| Pages (from-to) | 2010-2019 |
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| Journal | Multiple Sclerosis Journal |
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| Volume | 28 |
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| Issue number | 13 |
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| DOIs | |
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| Publication status | Published - 1 Nov 2022 |
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The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.H. receives research support from the Dutch MS Research Foundation. L.E.J. receives research support from Alzheimer Association, Alzheimer Netherlands, Michael J Fox Foundation, Stichting ParkinsonFonds, and Health Holland. H.E.H. receives research support from Dutch MS Research Foundation, ZonMW, NWO, ATARA, Biogen, Celgene/BMS, Merck, and MedDay; serves as a consultant for Sanofi Genzyme, Merck BV, Biogen Idec, Roche, and Novartis; and is on the editorial board of Multiple Sclerosis Journal. M.M.S. serves as an editorial board member of Frontiers in Neurology, received research support from the Dutch MS Research Foundation ARSEP, Eurostars-EUREKA, ZonMW, Amsterdam Neuroscience, Atara, Biogen, Celgene/BMS, Merck, and MedDay; and received consulting or speaking fees from ExceMed, Genzyme, Novartis, and Biogen. J.J.G.G. has served as a consultant for Merck-Serono, Biogen, Novartis, Genzyme, and Teva Pharmaceuticals; he has received research support from the Dutch MS Research Foundation, Ammodo, Eurostars-EUREKA, Biogen, Celgene/BMS, Merck, MedDay, and Novartis. Other authors report no competing interests.
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Dutch MS Research Foundation (grant nos. 14-358e and 16-954b), and MoveS foundation.
