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 schizophr… Show more
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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).…”
Evolutionarily conserved, peer‐directed social behaviors are essential to participate in many aspects of human society. These behaviors directly impact psychological, physiological, and behavioral maturation. Adolescence is an evolutionarily conserved period during which reward‐related behaviors, including social behaviors, develop via developmental plasticity in the mesolimbic dopaminergic “reward” circuitry of the brain. The nucleus accumbens (NAc) is an intermediate reward relay center that develops during adolescence and mediates both social behaviors and dopaminergic signaling. In several developing brain regions, synaptic pruning mediated by microglia, the resident immune cells of the brain, is important for normal behavioral development. We previously demonstrated that during adolescence, in rats, microglial synaptic pruning shapes the development of NAc and social play behavior in males and females. In this report, we hypothesize that interrupting microglial pruning in NAc during adolescence will have persistent effects on male and female social behavior in adulthood. We found that inhibiting microglial pruning in the NAc during adolescence had different effects on social behavior in males and females. In males, inhibiting pruning increased familiar exploration and increased nonsocial contact. In females, inhibiting pruning did not change familiar exploration behavior but increased active social interaction. This leads us to infer that naturally occurring NAc pruning serves to reduce social behaviors toward a familiar conspecific 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.…”
Section: Discussionmentioning
confidence: 99%
“…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).…”
Evolutionarily conserved, peer‐directed social behaviors are essential to participate in many aspects of human society. These behaviors directly impact psychological, physiological, and behavioral maturation. Adolescence is an evolutionarily conserved period during which reward‐related behaviors, including social behaviors, develop via developmental plasticity in the mesolimbic dopaminergic “reward” circuitry of the brain. The nucleus accumbens (NAc) is an intermediate reward relay center that develops during adolescence and mediates both social behaviors and dopaminergic signaling. In several developing brain regions, synaptic pruning mediated by microglia, the resident immune cells of the brain, is important for normal behavioral development. We previously demonstrated that during adolescence, in rats, microglial synaptic pruning shapes the development of NAc and social play behavior in males and females. In this report, we hypothesize that interrupting microglial pruning in NAc during adolescence will have persistent effects on male and female social behavior in adulthood. We found that inhibiting microglial pruning in the NAc during adolescence had different effects on social behavior in males and females. In males, inhibiting pruning increased familiar exploration and increased nonsocial contact. In females, inhibiting pruning did not change familiar exploration behavior but increased active social interaction. This leads us to infer that naturally occurring NAc pruning serves to reduce social behaviors toward a familiar conspecific in both males and females.
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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 …”
Section: Introductionmentioning
confidence: 99%
“…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).…”
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