CSMD1 regulates brain complement activity and circuit development

Matthew L Baum; Daniel K Wilton; Rachel G Fox; Alanna Carey; Yu-Han H Hsu; Ruilong Hu; Henna J Jäntti; Jaclyn B Fahey; Allie K Muthukumar; Nikkita Salla; William Crotty; Nicole Scott-Hewitt; Elizabeth Bien; David A Sabatini; Toby B Lanser; Arnaud Frouin; Frederick Gergits; Bjarte Håvik; Chrysostomi Gialeli; Eugene Nacu; Kasper Lage; Anna M Blom; Kevin Eggan; Steven A McCarroll; Matthew B Johnson; Beth Stevens

doi:10.1016/j.bbi.2024.03.041

CSMD1 regulates brain complement activity and circuit development

Brain Behav Immun. 2024 Mar 27:119:317-332. doi: 10.1016/j.bbi.2024.03.041. Online ahead of print.

Authors

Matthew L Baum¹, Daniel K Wilton², Rachel G Fox³, Alanna Carey², Yu-Han H Hsu⁴, Ruilong Hu⁵, Henna J Jäntti³, Jaclyn B Fahey², Allie K Muthukumar², Nikkita Salla⁵, William Crotty⁶, Nicole Scott-Hewitt², Elizabeth Bien⁷, David A Sabatini², Toby B Lanser², Arnaud Frouin², Frederick Gergits², Bjarte Håvik⁸, Chrysostomi Gialeli⁹, Eugene Nacu⁴, Kasper Lage⁴, Anna M Blom¹⁰, Kevin Eggan⁶, Steven A McCarroll¹¹, Matthew B Johnson¹², Beth Stevens¹³

Affiliations

¹ Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; MD-PhD Program of Harvard & MIT, Harvard Medical School, Boston, MA 02115, USA.
² Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
⁷ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Sollien 147A, 5096 Bergen, Norway.
⁹ Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, S-214 28 Malmö, Sweden; Cardiovascular Research - Translational Studies Research Group, Department of Clinical Sciences, Lund University, S-214 28 Malmö, Sweden.
¹⁰ Division of Medical Protein Chemistry, Department of Translational Medicine, Lund University, S-214 28 Malmö, Sweden.
¹¹ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹² Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: johnson@broadinstitute.org.
¹³ Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, USA. Electronic address: beth.stevens@childrens.harvard.edu.

PMID: 38552925
DOI: 10.1016/j.bbi.2024.03.041

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 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 brain during development.

Keywords: Complement cascade; Complement control protein; Neural circuits; Schizophrenia; Synaptic pruning.