Search

Complement system plays an important role in the immune defense against pathogens; however, recent studies demonstrated an important role of complement subunits C1q, C4, and C3 in normal functions of the central nervous system (CNS) such as non-functional synapse elimination (synapse pruning), and during various neurologic pathologies. Humans have two forms of C4 protein encoded by C4A and C4B genes that share 99.5% homology, while mice have only one C4B gene that is functionally active in the complement cascade. Overexpression of the human C4A gene was shown to contribute to the development of schizophrenia by mediating extensive synapse pruning through the activation C1q-C4-C3 pathway, while C4B deficiency or low levels of C4B expression were shown to relate to the development of schizophrenia and autism spectrum disorders possibly via other mechanisms not related to synapse elimination. To investigate the potential role of C4B in neuronal functions not related to synapse pruning, we compared wildtype (WT) mice with C3- and C4B- deficient animals for their susceptibility to pentylenetetrazole (PTZ)- induced epileptic seizures. We found that C4B (but not C3)-deficient mice were highly susceptible to convulsant and subconvulsant doses of PTZ when compared to WT controls. Further gene expression analysis revealed that in contrast to WT or C3-deficient animals, C4B-deficient mice failed to upregulate expressions of multiple immediate early genes (IEGs) Egrs1-4, c-Fos, c-Jus, FosB, Npas4, and Nur77 during epileptic seizures. Moreover, C4B-deficient mice had low levels of baseline expression of Egr1 on mRNA and protein levels, which was correlated with the cognitive problems of these animals. C4-deficient animals also failed to upregulate several genes downstream of IEGs such as BDNF and pro-inflammatory cytokines IL-1β, IL-6, and TNF. Taken together, our study demonstrates a new role of C4B in the regulation of expression of IEGs and their downstream targets during CNS insults such as epileptic seizures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Veremeyko, Jiang, He and Ponomarev.)

Twenty years ago, the scientific community exhibited relatively little interest in the study of microglial cells. However, recent technical and conceptual advances in this field have greatly increased interest in the basic biology of these cells within various neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, and traumatic brain/spinal cord injuries. The main functions of these cells in the normal central nervous system (CNS) remain poorly understood, despite considerable elucidation of their roles in pathological conditions. Microglia populate the brain before birth and remain in close lifelong contact with CNS-resident cells under the influence of the local microenvironment. Within the CNS parenchyma, microglia actively interact with two main cell types, astrocytes and neurons, which produce many factors that affect microglia phenotypes in the normal CNS and during neuroinflammation. These factors include interleukin (IL)-34, macrophage colony-stimulating factor, transforming growth factor-β, and IL-4, which promote microglial expansion, survival, and differentiation to an anti-inflammatory phenotype in the normal CNS. Under inflammatory conditions, however, astrocytes produce several pro-inflammatory factors that contribute to microglial activation. The interactions of microglia with neurons in the normal and diseased CNS are especially intriguing. Microglia are known to interact actively with neurons by facilitating axonal pruning during development, while neurons provide specific factors that alter microglial phenotypes and functions. This review focuses mainly on the roles of soluble neuronal factors that affect microglial phenotypes and functions and the possible involvement of these factors in the pathology of neurodegenerative diseases., (Copyright © 2019 Veremeyko, Yung, Dukhinova, Strekalova and Ponomarev.)