Inhibitory synaptic loss drives network changes in multiple sclerosis: An ex vivo to in silico translational study

Multiple Sclerosis Journal, vol. 28, pp. 2010–2019

Abstract

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.

Authors 11

1. Marijn Huiskamp corresponding

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands

2. Svenja Kiljan

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

3. Shanna D. Kulik

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

4. Maarten E. Witte

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Molecular Cell Biology and Inflammation, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

5. Laura E. Jonkman

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

6. John G. J. M. Bol

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

7. Geert J. Schenk

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

8. Hanneke E. Hulst Aachen Anatomy and Neurosciences MS Center Amsterdam Medical and Neuropsychology Unit Institute of Psychology, Leiden University

   Leiden University · Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands/Health, Medical and Neuropsychology Unit, Institute of Psychology, Leiden University, Leiden, The Netherlands

9. Prejaas K. B. Tewarie

   Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

   Affiliation as printed

   Neurology, MS center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands/Clinical Neurophysiology and MEG Center, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

10. Menno Michiel Schoonheim

    Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands

11. Jeroen J.G. Geurts

    Amsterdam Neuroscience · Vrije Universiteit Amsterdam · Amsterdam UMC Location Vrije Universiteit Amsterdam

    Affiliation as printed

    Anatomy and Neurosciences, MS Center Amsterdam, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam UMC location VUmc, Amsterdam, The Netherlands