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      The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis

      research-article
      , DPhil,MRCPsych 1 , 2 , , MD 1 , , PhD 1 , , PhD 3 , , MD PhD 3
      Molecular psychiatry

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          Abstract

          The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally-derived antigens. Abnormalities in complement functions occur in many infectious and auto-immune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A ( C4A) and 4B ( C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the ‘staging posts’ for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to auto-immune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.

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          Most cited references112

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          Regional differences in synaptogenesis in human cerebral cortex.

          The formation of synaptic contacts in human cerebral cortex was compared in two cortical regions: auditory cortex (Heschl's gyrus) and prefrontal cortex (middle frontal gyrus). Synapse formation in both cortical regions begins in the fetus, before conceptual age 27 weeks. Synaptic density increases more rapidly in auditory cortex, where the maximum is reached near postnatal age 3 months. Maximum synaptic density in middle frontal gyrus is not reached until after age 15 months. Synaptogenesis occurs concurrently with dendritic and axonal growth and with myelination of the subcortical white matter. A phase of net synapse elimination occurs late in childhood, earlier in auditory cortex, where it has ended by age 12 years, than in prefrontal cortex, where it extends to midadolescence. Synaptogenesis and synapse elimination in humans appear to be heterochronous in different cortical regions and, in that respect, appears to differ from the rhesus monkey, where they are concurrent. In other respects, including overproduction of synaptic contacts in infancy, persistence of high levels of synaptic density to late childhood or adolescence, the absolute values of maximum and adult synaptic density, and layer specific differences, findings in the human resemble those in rhesus monkeys.
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            Synaptic density in human frontal cortex - developmental changes and effects of aging.

            Density of synaptic profiles in layer 3 of middle frontal gyrus was quantitated in 21 normal human brains ranging from newborn to age 90 years. Synaptic profiles could be reliably demonstrated by the phosphotungstic acid method (Bloom and Aghajanian) in tissue fixed up to 36 h postmortem. Synaptic density was constant throughout adult life (ages 16--72 years) with a mean of 11.05 X 10(8) synapses/cu.mm +/- 0.41 S.E.M. There was a slight decline in synaptic density in brains of the aged (ages 74--90 years) with a mean of 9.56 X 10(8) synapses/cu.mm +/- 0.28 S.E.M. in 4 samples (P less than 0.05). Synaptic density in neonatal brains was already high--in the range seen in adults. However, synaptic morphology differed; immature profiles had an irregular presynaptic dense band instead of the separate presynaptic projections seen in mature synapses. Synaptic density increased during infancy, reaching a maximum at age 1--2 years which was about 50% above the adult mean. The decline in synaptic density observed between ages 2--16 years was accompanied by a slight decrease in neuronal density. Human cerebral cortex is one of a number of neuronal systems in which loss of neurons and synapses appears to occur as a late developmental event.
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              A dramatic increase of C1q protein in the CNS during normal aging.

              The decline of cognitive function has emerged as one of the greatest health threats of old age. Age-related cognitive decline is caused by an impacted neuronal circuitry, yet the molecular mechanisms responsible are unknown. C1q, the initiating protein of the classical complement cascade and powerful effector of the peripheral immune response, mediates synapse elimination in the developing CNS. Here we show that C1q protein levels dramatically increase in the normal aging mouse and human brain, by as much as 300-fold. This increase was predominantly localized in close proximity to synapses and occurred earliest and most dramatically in certain regions of the brain, including some but not all regions known to be selectively vulnerable in neurodegenerative diseases, i.e., the hippocampus, substantia nigra, and piriform cortex. C1q-deficient mice exhibited enhanced synaptic plasticity in the adult and reorganization of the circuitry in the aging hippocampal dentate gyrus. Moreover, aged C1q-deficient mice exhibited significantly less cognitive and memory decline in certain hippocampus-dependent behavior tests compared with their wild-type littermates. Unlike in the developing CNS, the complement cascade effector C3 was only present at very low levels in the adult and aging brain. In addition, the aging-dependent effect of C1q on the hippocampal circuitry was independent of C3 and unaccompanied by detectable synapse loss, providing evidence for a novel, complement- and synapse elimination-independent role for C1q in CNS aging.
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                Author and article information

                Journal
                9607835
                20545
                Mol Psychiatry
                Mol. Psychiatry
                Molecular psychiatry
                1359-4184
                1476-5578
                24 May 2017
                01 August 2017
                November 2017
                01 February 2018
                : 22
                : 11
                : 1554-1561
                Affiliations
                [1 ]Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, PA
                [2 ]Department of Human Genetics, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA
                [3 ]Stanley Division of Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Md
                Author notes
                [* ]Corresponding author: Vishwajit L Nimgaonkar, 3811 O’Hara St, TDH Room 441, Pittsburgh, PA 15213. nimga@ 123456pitt.edu , phone 412-246-6353, fax 412-246-6350
                Article
                NIHMS877404
                10.1038/mp.2017.151
                5656502
                28761078
                e4a1e5cb-aca9-45fa-a093-ab405f46c8ec

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                Molecular medicine
                Molecular medicine

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