Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

CSMD1 regulates brain complement activity and circuit development

Baum, Matthew L ; Wilton, Daniel K ; Fox, Rachel G ; Carey, Alanna ; Hsu, Yu-Han H ; Hu, Ruilong ; Jäntti, Henna J ; Fahey, Jaclyn B ; Muthukumar, Allie K and Salla, Nikkita , et al. (2024) In Brain, Behavior, and Immunity
Abstract

Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined... (More)

Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined Csmd1-knockout mice and CSMD1-knockout human stem cell-derived neurons. We interrogated synapse and circuit development of the mouse visual thalamus, a process that involves complement pathway activity. We also quantified complement deposition on synapses in mouse visual thalamus and on cultured human neurons. Finally, we assessed uptake of synaptosomes by cultured microglia. We found that CSMD1 is present at synapses and interacts with complement proteins in the brain. Mice lacking Csmd1 displayed increased levels of complement component C3, an increased colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and aberrant segregation of eye-specific retinal inputs to the visual thalamus during the critical period of complement-dependent refinement of this circuit. Loss of CSMD1 in vivo enhanced synaptosome engulfment by microglia in vitro, and this effect was dependent on activity of the microglial complement receptor, CR3. Finally, human stem cell-derived neurons lacking CSMD1 were more vulnerable to complement deposition. These data suggest that CSMD1 can function as a regulator of complement-mediated synapse elimination in the CNS during development.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Brain, Behavior, and Immunity
publisher
Elsevier
external identifiers
  • scopus:85190131685
  • pmid:38552925
ISSN
1090-2139
DOI
10.1016/j.bbi.2024.03.041
language
English
LU publication?
yes
additional info
Copyright © 2024. Published by Elsevier Inc.
id
66985240-d8ec-40e0-97ed-666bf2748d39
date added to LUP
2024-04-03 21:45:28
date last changed
2024-04-23 11:07:38
@article{66985240-d8ec-40e0-97ed-666bf2748d39,
  abstract     = {{<p>Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined Csmd1-knockout mice and CSMD1-knockout human stem cell-derived neurons. We interrogated synapse and circuit development of the mouse visual thalamus, a process that involves complement pathway activity. We also quantified complement deposition on synapses in mouse visual thalamus and on cultured human neurons. Finally, we assessed uptake of synaptosomes by cultured microglia. We found that CSMD1 is present at synapses and interacts with complement proteins in the brain. Mice lacking Csmd1 displayed increased levels of complement component C3, an increased colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and aberrant segregation of eye-specific retinal inputs to the visual thalamus during the critical period of complement-dependent refinement of this circuit. Loss of CSMD1 in vivo enhanced synaptosome engulfment by microglia in vitro, and this effect was dependent on activity of the microglial complement receptor, CR3. Finally, human stem cell-derived neurons lacking CSMD1 were more vulnerable to complement deposition. These data suggest that CSMD1 can function as a regulator of complement-mediated synapse elimination in the CNS during development.</p>}},
  author       = {{Baum, Matthew L and Wilton, Daniel K and Fox, Rachel G and Carey, Alanna and Hsu, Yu-Han H and Hu, Ruilong and Jäntti, Henna J and Fahey, Jaclyn B and Muthukumar, Allie K and Salla, Nikkita and Crotty, William and Scott-Hewitt, Nicole and Bien, Elizabeth and Sabatini, David A and Lanser, Toby B and Frouin, Arnaud and Gergits, Frederick and Håvik, Bjarte and Gialeli, Chrysostomi and Nacu, Eugene and Lage, Kasper and Blom, Anna M and Eggan, Kevin and McCarroll, Steven A and Johnson, Matthew B and Stevens, Beth}},
  issn         = {{1090-2139}},
  language     = {{eng}},
  month        = {{03}},
  publisher    = {{Elsevier}},
  series       = {{Brain, Behavior, and Immunity}},
  title        = {{CSMD1 regulates brain complement activity and circuit development}},
  url          = {{http://dx.doi.org/10.1016/j.bbi.2024.03.041}},
  doi          = {{10.1016/j.bbi.2024.03.041}},
  year         = {{2024}},
}