Complement-associated loss of CA2 inhibitory synapses in the demyelinated hippocampus impairs memory

Valeria Ramaglia*, Mohit Dubey, M. Alfonso Malpede, Naomi Petersen, Sharon I. de Vries, Shanzeh M. Ahmed, Dennis S.W. Lee, Geert J. Schenk, Stefan M. Gold, Inge Huitinga, Jennifer L. Gommerman, Jeroen J.G. Geurts, Maarten H.P. Kole

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The complement system is implicated in synapse loss in the MS hippocampus, but the functional consequences of synapse loss remain poorly understood. Here, in post-mortem MS hippocampi with demyelination we find that deposits of the complement component C1q are enriched in the CA2 subfield, are linked to loss of inhibitory synapses and are significantly higher in MS patients with cognitive impairments compared to those with preserved cognitive functions. Using the cuprizone mouse model of demyelination, we corroborated that C1q deposits are highest within the demyelinated dorsal hippocampal CA2 pyramidal layer and co-localized with inhibitory synapses engulfed by microglia/macrophages. In agreement with the loss of inhibitory perisomatic synapses, we found that Schaffer collateral feedforward inhibition but not excitation was impaired in CA2 pyramidal neurons and accompanied by intrinsic changes and a reduced spike output. Finally, consistent with excitability deficits, we show that cuprizone-treated mice exhibit impaired encoding of social memories. Together, our findings identify CA2 as a critical circuit in demyelinated intrahippocampal lesions and memory dysfunctions in MS.

Original languageEnglish
Pages (from-to)643-667
Number of pages25
JournalActa Neuropathologica
Volume142
DOIs
Publication statusPublished - Oct 2021

Bibliographical note

Funding Information:
The study has been funded by the National Multiple Sclerosis Society (RG-1602–07777) to V.R. and M.K. and the Netherlands Organization for Scientific Research (NWO Vici 865.17.003) to M.K. The funding agents did not play a role in the study design.

Publisher Copyright:
© 2021, Crown.

Funding

The study has been funded by the National Multiple Sclerosis Society (RG-1602–07777) to V.R. and M.K. and the Netherlands Organization for Scientific Research (NWO Vici 865.17.003) to M.K. The funding agents did not play a role in the study design.

Keywords

  • Complement
  • Demyelination
  • Hippocampus
  • Microglia
  • Multiple sclerosis
  • Synapses

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