Complement Dependent Synaptic Reorganisation During Critical Periods of Brain Development and Risk for Psychiatric Disorder

Abstract

We now know that the immune system plays a major role in the complex processes underlying brain development throughout the lifespan, carrying out a number of important homeostatic functions under physiological conditions in the absence of pathological inflammation or infection. In particular, complement-mediated synaptic pruning during critical periods of early life may play a key role in shaping brain development and subsequent risk for psychopathology, including neurodevelopmental disorders such as schizophrenia and autism spectrum disorders. However, these disorders vary greatly in their onset, disease course, and prevalence amongst sexes suggesting complex interactions between the immune system, sex and the unique developmental trajectories of circuitries underlying different brain functions which are yet to be fully understood. Perturbations of homeostatic neuroimmune interactions during different critical periods in which regional circuits mature may have a plethora of long-term consequences for psychiatric phenotypes, but at present there is a gap in our understanding of how these mechanisms may impact on the structural and functional changes occurring in the brain at different developmental stages. In this article we will consider the latest developments in the field of complement mediated synaptic pruning where our understanding is beginning to move beyond the visual system where this process was first described, to brain areas and developmental periods of potential relevance to psychiatric disorders.

Synaptic pruning during adolescence shapes adult social behavior in both males and females

“…Critically, dysregulated synaptic pruning during adolescence plays a role in the development of psychotic disorders (Germann et al., 2021). Schizophrenia, in particular, with the onset of psychotic episodes and other hallmarks of the disorder strongly linked to microglial overactivation (Rodrigues‐Neves et al., 2022; Sellgren et al., 2019) and complement system signaling (Wang et al., 2019; Westacott & Wilkinson, 2022). Taken together, these findings suggest that interfering with complement‐mediated microglial pruning might delay symptoms and the onset of schizophrenia.…”

“…In several developing brain regions, complement system proteins (e.g., C3) facilitate synaptic pruning by binding to complement receptor 3 (CR3) on microglia, the resident immune cells of the brain (Grabert et al., 2016; Schafer et al., 2012; Soteros & Sia, 2022). Sex‐specificity exists in microglial activity (Lenz et al., 2013; Han et al, 2021) and complement‐mediated pruning (Prilutsky et al, 2017; Westacott & Wilkinson, 2022) during adolescence. More specifically, we demonstrated in rats that C3‐microglial synaptic pruning mediates NAc and social development during sex‐specific adolescent periods: pre‐to‐early adolescence in females (postnatal day (P)22–30) and early‐to‐mid adolescence in males (P30–40), and via sex‐specific synaptic pruning targets (dopamine D1 receptors in males, but not females) (Kopec et al., 2018).…”

The correlates of neonatal complement component 3 and 4 protein concentrations with a focus on psychiatric and autoimmune disorders

“…The relationship between C3-related measures and both psychiatric and autoimmune disorders was uniformly null, apart from a single post-hoc finding that higher circulating C3 protein concentration was associated with a decreased risk of schizophrenia in females only. C3 has been implicated in synaptic pruning, 11 , 12 , 13 , 14 , 15 and evidence suggests that estrogen may influence C3-related activation of microglia and subsequent phagocytosis of synapsis. 40 We hope that this finding can guide future hypothesis-driven research.…”

“…These findings are of interest with regard to neurodevelopmental disorders such as schizophrenia (SCZ), given evidence that C4 and related members of the complement systems (e.g., C1q, C3) are involved in synaptic pruning during brain development. 11 , 12 , 13 , 14 , 15 …”

“…Apart from C4, there is evidence that complement component C3 (encoded by the C3 gene) is also involved in synaptic pruning, 11 , 12 , 13 , 14 , 15 and both C4 and C3 protein concentrations are often used in the monitoring of autoimmune disorders. 18 It is thus of interest to measure additional members of this cascade (e.g., C3 is immediately downstream of C4).…”