Autoantibodies against NCAM1 from patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice

Shiwaku, Hiroki; Katayama, S; Kondo, Kanoh; Nakano, Yoshikatsu; Tanaka, Hikari; Yoshioka, Yuki; Fujita, Kyota; Tamaki, Haruna; Takebayashi, Hironao; Terasaki, Omi; Nagase, Yukihiro; Nagase, Teruyoshi; Ishikawa, Kinya; Okazawa, Hitoshi; Takahashi, Hidehiko

doi:10.1016/j.xcrm.2022.100597

Cited by 19 publications

(15 citation statements)

References 81 publications

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“…More large-scale studies are therefore necessary to investigate any systematic age effect that might affect our findings. Surprisingly, we have also detected a higher proportion of patients with a paranoid hallucinatory syndrome in the group of psychiatric patients without neural autoantibodies as a tendency, a finding that contradicts previous reports on autoantibody-mediated psychosis in patients (18)(19)(20)(21) and animal models (10) and that might depend on cohort size; this result should be replicated in larger cohorts. Another limitation is that we did not systematically screen for any head injuries, none of the patients' clinical data suggested any trauma.…”

Section: Limitationscontrasting

confidence: 99%

“…The following autoantibodies in patients were determined as a standard panel in serum and/or CSF via Euroline immunoblots and cell-based assays [autoantibodies against intracellular autoantibodies: amphiphysin, CV2, GAD65, HuD, Ma1/Ma2, neurochondrin (NC), Ri, TR, Yo, and Zic4; autoantibodies against cell surface targets: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors 1/2 (AMPAR1/2), Aquaporin 4, contactin-associated protein 2 (CASPR2), dipeptidyl-peptidase-like 6 protein (DPPX), gamma-aminobutyric acid B1/2 receptor (GABAB1/2R), glutamic acid decarboxylase (GAD65), Leucin Rich Glioma Inactivated Protein 1 (LGI1), N-methyl-D-aspartate receptor (NMDAR)]. This standard panel of autoantibodies was determined in all the patients by assessing the most relevant neural autoantibodies against membrane-surface and intracellular antigens, although it would make sense to assess only specific autoantibodies in association with specific psychiatric diseases, i.e., anti-basal ganglia antibodies in obsessive-compulsive disorder ( 9 ) or neural cell adhesion molecule 1 antibodies in patients with schizophrenia ( 10 ) to limit costs. However, there is no evidence to date of clear types of autoantibodies that are specific to only one psychiatric condition ( 4 ).…”

Section: Methodsmentioning

confidence: 99%

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City Environment and Occurrence of Neural Autoantibodies in Psychiatric Patients

et al. 2022

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BackgroundCity living might lead to a higher risk of psychiatric disease, but to date there is no evidence of any correlation between an urban environment and the occurrence of neural autoantibodies in psychiatric disease. Our aim is to identify whether the number of patients with and without neural autoantibodies living in diverse rural and urban environments differ.MethodsWe enrolled retrospectively a cohort of 167 psychiatric patients via a cross-sectional design from the Department of Psychiatry and Psychotherapy University Medical Center Göttingen and determined serum and/or CSF neural autoantibodies in them. The patients live in the German states of Lower Saxony, Thuringia, and Hessen. Their data were investigated in conjunction with the location of their primary residence. We categorized them into five different categories depending upon their primary residence: one rural and four different urban environments depending on their population numbers.ResultsWe identified 36 psychiatric patients with neural autoantibodies, and 131 psychiatric patients with none. In total, 24 psychiatric patients with neural autoantibodies were classified as sharing a possible, probable, or definitive autoimmune origin according to our recently set criteria. We observed as a non-significant trend that more psychiatric patients with neural autoantibodies and a probable or definitive autoimmune origin (45.8%) live in a major city with over 100,000 inhabitants than do psychiatric patients presenting no evidence of autoantibodies (26.4%). However, we identified no relevant differences between (1) psychiatric patients with and without neural autoantibodies or between (2) psychiatric patients with a possible, probable, or definitive autoimmune origin and those without such autoantibodies in relation to the diverse rural and urban environmental settings.ConclusionThe inherently different aspects of rural and urban environments do not appear to be relevant in determining the frequency of neural autoantibodies in psychiatric patients in Lower Saxony, Thuringia, and Hessen in Germany. Furthermore, large-scale studies involving other states across Germany should be conducted to exclude any regional differences and to examine the tendency of a higher frequency in large cities of autoimmune-mediated psychiatric syndromes.

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Section: Limitationscontrasting

confidence: 99%

Section: Methodsmentioning

confidence: 99%

City Environment and Occurrence of Neural Autoantibodies in Psychiatric Patients

et al. 2022

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“…Interestingly, defects in many of the novel myelinogenic molecules we identified in this study have been implicated in neuropsychiatric conditions. SNPs in NCAM1 contribute to differential risk of developing bipolar disorder and schizophrenia 48 , and, recently, autoantibodies against NCAM1 were found in patients with schizophrenia 49 . Moreover, disruption in the Wnt and FGF signaling pathways, which are activated by Rspo3 and NCAM1 / Fgf18 , respectively, have been observed in patients with schizophrenia, bipolar disorder, and major depressive disorder 50,51 .…”

Section: Discussionmentioning

confidence: 99%

Neuronal-class specific molecular cues drive differential myelination in the neocortex

Jokhi,

Domínguez-Iturza,

Kim

et al. 2024

Preprint

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In the neocortex, oligodendrocytes produce distinct amounts of myelin in each cortical layer and along the axons of individual neuron types. Here we present a comprehensive single-cell molecular map of mouse cortical oligodendrocytes across different cortical layers and stages of myelination, spanning the initiation of cortical myelination into adulthood. We apply this dataset to show that neuron-class specific signals drive oligodendrocyte maturation and differential myelination across cortical layers. We find that each layer contains a similar compendium of oligodendrocyte classes, indicating that oligodendrocyte heterogeneity cannot explain layer-specific myelination. To evaluate whether neuronal diversity drives differential myelination across cortical layers, we generated a predicted ligand-receptor interactome between projection neuron types and oligodendrocyte states, across cortical layers and time.In vivofunctional testing identifiedFgf18,Ncam1, andRspo3as novel, neuron-derived pro-myelinating signals. Our results highlight neuron-class-dependent control of myelin distribution in the neocortex.

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“…Variants of the gene encoding NCAM1 have been associated with schizophrenia and bipolar disorder 45,46 , and NCAM1 knockout and transgenic mice display changes in behaviour related to neuropsychiatric disorder 47,48 . A recent study demonstrated that anti-NCAM1 autoantibodies in patients with schizophrenia induced schizophrenia-related behaviour and inhibited the formation of synapses in mice, concluding that these antibody proteins may be a potential therapeutic target 49 . Our nding that CD40 is associated with schizophrenia also implicates immune processes in psychiatric illness aetiology as it is a transmembrane protein found on antigen-presenting cells, which is required for activation of adaptive immune cells.…”

Section: Discussionmentioning

confidence: 99%

Associations of 2,922 genetically predicted plasma protein levels with mental illness and response to treatment

Zhang,

Chidiac,

Zhao

et al. 2024

Preprint

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There is growing evidence that mental disorders are associated with altered levels of plasma proteins, potentially indicating molecular targets for drug development or repurposing, but determining which associations are due to confounding and which are causal for illness onset or course is challenging. We used two-sample Mendelian randomisation, which can examine associations free from the effects of confounding between genetically predicted levels of the blood proteome and multiple psychiatric traits. We used the UK Biobank’s largest genome-wide association study (GWAS) of 2,922 plasma proteins, selecting lead cis-quantitative trait loci variants as genetic instruments. We report 337 false discovery rate (FDR) corrected associations of plasma proteins involved in immunity, cytoskeletal integrity, and vesicular trafficking with psychiatric traits: 188 with schizophrenia, 86 with bipolar disorder, 32 with opioid use disorder, 30 with major depressive disorder, and one with treatment resistance in depression. Immune-metabolic protein BTN2A1 associated with depression, schizophrenia, and bipolar disorder. We did not find strong evidence for obsessive compulsive disorder, panic disorder, treatment resistance in schizophrenia, or the depression trait antidepressant response rate of improvement. Colocalisation analyses were applied to the above results and provided evidence for 33 associations that are less likely to be due to horizontal pleiotropy. Our results can help to inform efforts toward identifying potential aetiological pathways of mental disorders and assist in drug development or repurposing.

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Autoantibodies against NCAM1 from patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice

Cited by 19 publications

References 81 publications

City Environment and Occurrence of Neural Autoantibodies in Psychiatric Patients

City Environment and Occurrence of Neural Autoantibodies in Psychiatric Patients

Neuronal-class specific molecular cues drive differential myelination in the neocortex

Associations of 2,922 genetically predicted plasma protein levels with mental illness and response to treatment

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