Schizophrenia: Complement Cleaning or Killing

Abstract

Schizophrenia is a psychiatric disorder with a typical onset occurring during adolescence or young adulthood. The heterogeneity of the disorder complicates our understanding of the pathophysiology. Reduced cortical synaptic densities are commonly observed in schizophrenia and suggest a role for excessive synaptic elimination. A major pathway hypothesised to eliminate synapses during postnatal development is the complement system. This review provides an overview of genetic and functional evidence found for the individual players of the classical complement pathway. In addition, the consequences of the absence of complement proteins, in the form of complement protein deficiencies in humans, are taken into consideration. The collective data provide strong evidence for excessive pruning by the classical complement pathway, contributing to cognitive impairment in schizophrenia. In future studies, it will be important to assess the magnitude of the contribution of complement overactivity to the occurrence and prevalence of phenotypic features in schizophrenia. In addition, more insight is required for the exact mechanisms by which the complement system causes excessive pruning, such as the suggested involvement of microglial engulfment and degradation of synapses. Ultimately, this knowledge is a prerequisite for the development of therapeutic interventions for selective groups of schizophrenia patients.

Neuroinflammation and schizophrenia – is there a link?

“…Steen and colleagues (2023) identified common genetic markers associated with both schizophrenia and systemic immune alterations ( 32 ). MIA can lead to methylation changes in schizophrenia-related genes, thus affecting susceptibility through genetic and environmental risk factors ( 33 , 34 ).…”

Connecting the Neurobiology of Developmental Brain Injury: Neuronal Arborisation as a Regulator of Dysfunction and Potential Therapeutic Target

“…In schizophrenic patients, during puberty, cortical thinning occurs at a faster pace and extends to neighbouring regions compared to age matched controls [ 45 ]. The reason for the excessive thinning has been proposed to be either due to reduced dendritic branching and decreased cell number, or more commonly due to excessive synaptic pruning or irregular synaptic remodelling [ 46 , 47 ]. From this information, we can conclude that a failure to maintain correct dendritic maturation leads to abnormal neuronal function and circuit establishment, which ultimately results in the development of atypical behavioural symptoms associated with neurodevelopmental disorders.…”

Special Issue: Genetics of Psychiatric Disease and the Basics of Neurobiology

“…The recent identification of Np as a decisive component of plasma membrane Ca 2+ ATPase complexes has opened the way to novel perspectives for the mechanistic understanding of learning and memory processes, and, thus, as a novel therapeutic target. In line with the hypothesis that disruptions to the immune system contribute to the development of schizophrenia, the review by Hogenaar and van Bokhoven addressed the question whether the classical pathway hyperactivity of the complement system contributes to the pathophysiology of schizophrenia through excessive synaptic pruning during postnatal development [ 10 ].…”