Complement System in Brain Architecture and Neurodevelopmental Disorders

Abstract

Current evidence indicates that certain immune molecules such as components of the complement system are directly involved in neurobiological processes related to brain development, including neurogenesis, neuronal migration, synaptic remodeling, and response to prenatal or early postnatal brain insults. Consequently, complement system dysfunction has been increasingly implicated in disorders of neurodevelopmental origin, such as schizophrenia, autism spectrum disorder (ASD) and Rett syndrome. However, the mechanistic evidence for a causal relationship between impaired complement regulation and these disorders varies depending on the disease involved. Also, it is still unclear to what extent altered complement expression plays a role in these disorders through inflammation-independent or-dependent mechanisms. Furthermore, pathogenic mutations in specific complement components have been implicated in the etiology of 3MC syndrome, a rare autosomal recessive developmental disorder. The aims of this review are to discuss the current knowledge on the roles of the complement system in sculpting brain architecture and function during normal development as well as after specific inflammatory insults, such as maternal immune activation (MIA) during pregnancy, and to evaluate the existing evidence associating aberrant complement with developmental brain disorders.

Sex Differences of Microglia and Synapses in the Hippocampal Dentate Gyrus of Adult Mouse Offspring Exposed to Maternal Immune Activation

“…In our work, we saw reductions in hippocampal expression of C1q and C3 following mIA, across sexes, and also with protein levels of C1q, in neurons. These reductions could reflect a decrease in complement-mediated synaptic elimination (Stevens et al, 2007;Druart and Le Magueresse, 2019;Sellgren et al, 2019;Magdalon et al, 2020;Tenner, 2020). However, unlike the gene expression, C3 protein levels are increased with mIA across both sexes.…”

A case report of complement C4B deficiency in a patient with steroid and IVIG-refractory anti-NMDA receptor encephalitis

“…This would be relevant because complement activation on autologous cells are tightly controlled and mostly stop after the deposition of C4b. We postulate that C4B deficiency in our patient might have led to the defective removal of immune complexes and possibly impairment of yet to be characterized neurogenic pathways, which has a substantial role in autoimmune encephalitis [9][10][11]. Complement deficiency is ameliorated by plasmapheresis, which normally correct the complement deficiency, but not by IVIG.…”

Synaptic Pruning in Schizophrenia: Does Minocycline Modulate Psychosocial Brain Development?

“…The possible role of aberrant immune functions involving altered neuroinflammatory processes is currently among the most intriguing topics in psychiatry. [ 109,110 ] Social defeat—especially when severe, chronic, inescapable, and demoralizing—is a desperate experience that can be characterized as an emotionally “inflamed” state. We propose that it is not a coincidence that microglia utilize a suite of inflammatory biochemical mechanisms to refine the circuits underlying the human social self.…”