Scientific References
Nature Communications
Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia
Gracias J, Orhan F, Hörbeck E, Holmén-Larsson J, Khanlarkani N, Malwade S, Goparaju SK, Schwieler L, Demirel İŞ, Fu T, Fatourus-Bergman H, Pelanis A, Goold CP, Goulding A, Annerbrink K, Isgren A, Sparding T, Schalling M, Yañez VAC, Göpfert JC, Nilsson J, Brinkmalm A, Blennow K, Zetterberg H, Engberg G, Piehl F, Sheridan SD, Perlis RH, Cervenka S, Erhardt S, Landen M, Sellgren CM
2022 PMID: 36329007
Read this PublicationPostsynaptic density is reduced in schizophrenia, and risk variants increasing complement component 4A (C4A) gene expression are linked to excessive synapse elimination. In two independent cohorts, we show that cerebrospinal fluid (CSF) C4A concentration is elevated in patients with first-episode psychosis (FEP) who develop schizophrenia (FEP-SCZ: median 0.41 fmol/ul [CI = 0.34-0.45], FEP-non-SCZ: median 0.29 fmol/ul [CI = 0.22-0.35], healthy controls: median 0.28 [CI = 0.24-0.33]). We show that the CSF elevation of C4A in FEP-SCZ exceeds what can be expected from genetic risk variance in the C4 locus, and in patient-derived cellular models we identify a mechanism dependent on the disease-associated cytokines interleukin (IL)-1beta and IL-6 to selectively increase neuronal C4A mRNA expression. In patient-derived CSF, we confirm that IL-1beta correlates with C4A controlled for genetically predicted C4A RNA expression (r = 0.39; CI: 0.01-0.68). These results suggest a role of C4A in early schizophrenia pathophysiology.
Biological Psychiatry
A Critical Perspective on the Synaptic Pruning Hypothesis of Schizophrenia Pathogenesis
Johnson MB, Hyman SE
2022 PMID: 35105471
Read this PublicationSchizophrenia characteristically begins during adolescence—like many psychiatric disorders (2)—starting with cognitive impairments and deficit symptoms followed by psychosis. Schizophrenia is highly heterogeneous in onset, symptom severity, mood disturbances, comorbidities, treatment response, and outcomes. It is also highly polygenic, which likely precludes a unitary pathophysiologic process because loading of risk alleles and relevant environmental exposures represents a complex stochastic grab bag. There are not, however, an infinite number of processes that could produce adolescent onset of unremitting cognitive and deficit symptoms followed by relapsing and remitting psychosis. In short, diverse affected pathways likely converge on a smaller number of basic mechanisms. Based on the evidence to date, arguably a leading candidate mechanism is the synaptic pruning hypothesis.
Nature Neuroscience
Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice
Yilmaz M, Yalcin E, Presumey J, Aw E, Ma M, Whelan CW, Stevens B, McCarroll SA, Carroll MC.
2021 PMID: 33353966
Read this PublicationThe complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.
Psychiatry Resarch
Securing direct stakeholder feedback to inform clinical research in serious mental illness: Results of a patient and family perspectives survey
Stafford E, Jakob S, Gur RE, Corcoran CM, Bearden CE
2023 PMID: 37924772
Read this PublicationMental illness research routinely includes unfamiliar or potentially frightening procedures like lumbar puncture (LP), contributing to low enrollment and retention. Previous studies related to LP acceptance have focused on older individuals, and little information on participant preferences for educational materials is available. We developed an online survey assessing existing knowledge, comfort and concerns, and preferences for educational materials in the context of our clinical study on schizophrenia spectrum conditions (SSCs). We found that participants were generally knowledgeable and interested in engaging with clinical SSC research. Frequency of engagement with research publications differed significantly by participant groups and age. Comfort levels were consistently highest for study procedures other than LP, though surprisingly the average number of informational needs per procedure was not significantly different for LP compared to other procedures. Preferences for format and source of educational materials varied across participant groups and age. Our results suggest that younger individuals with an SSC diagnosis are likely to have limited exposure to information, and proactively providing accessible and accurate educational materials may improve positive perceptions of LP. Providing content in a range of formats and sources will ensure that participants and their support networks have access to their preferred resources.
NAMI Advocate Magazine
The Importance of Biomarkers For Understanding and Treating Mental Illness
Hyman S, Johnson M, Jakob S
2023
Read this PublicationThe genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
Journal of Psychiatric Research
Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence?
Feinberg I
1983 PMID: 7187776
Read this PublicationConverging evidence indicates that a profound reorganization of human brain function takes place during adolescence: the amount of deep sleep and the rate of brain metabolism fall sharply; the latency of certain event-related potentials declines; the capacity to recover function after brain injury diminishes; and adult problem-solving 'power' appears. A reduction in cortical synaptic density has recently been observed and might account for all of these changes. Such synaptic 'pruning' may be analogous to the programmed elimination of neural elements in very early development. A defect in this maturational process may underlie those cases of schizophrenia that emerge during adolescence.
Neuron
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B
2012 PMID: 22632727
Read this PublicationMicroglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.
Neuron
Microglia Sculpt Postnatal Neural Circuits in an Activity and Complement-Dependent Manner
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B
2012 PMID: 22632727
Read this PublicationMicroglia are the resident CNS immune cells and active surveyors of the extracellular environment. While past work has focused on the role of these cells during disease, recent imaging studies reveal dynamic interactions between microglia and synaptic elements in the healthy brain. Despite these intriguing observations, the precise function of microglia at remodeling synapses and the mechanisms that underlie microglia-synapse interactions remain elusive. In the current study, we demonstrate a role for microglia in activity-dependent synaptic pruning in the postnatal retinogeniculate system. We show that microglia engulf presynaptic inputs during peak retinogeniculate pruning and that engulfment is dependent upon neural activity and the microglia-specific phagocytic signaling pathway, complement receptor 3(CR3)/C3. Furthermore, disrupting microglia-specific CR3/C3 signaling resulted in sustained deficits in synaptic connectivity. These results define a role for microglia during postnatal development and identify underlying mechanisms by which microglia engulf and remodel developing synapses.
Nature
Schizophrenia risk from complex variation of complement component 4
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, Tooley K, Presumey J, Baum M, Van Doren V, Genovese G, Rose SA, Handsaker RE; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Daly MJ, Carroll MC, Stevens B, McCarroll SA
2016 PMID: 26814963
Read this PublicationSchizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.
Nature
Pruning hypothesis comes of age
Johnson MB, Stevens B
2018 PMID: 32094942
Read this PublicationThe idea that disrupted pruning of neuronal connections in the brain during adolescence is a cause of schizophrenia was proposed in 1983. This proved prescient, as subsequent imaging, genetic and molecular research has shown.