Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

Stepniak, Beata; Kästner, Anne; Poggi, Giulia; Mitjans, Marina; Begemann, Martin; Hartmann, Annette M.; Auwera, Sandra Van der; Sananbenesi, Farahnaz; Krueger‐Burg, Dilja; Matuszko, Gabriela; Brosi, Cornelia; Homuth, Georg; Völzke, Henry; Benseler, Fritz; Bagni, Claudia; Fischer, Utz; Dityatev, Alexander; Grabe, Hans‐Jörgen; Rujescu, Dan; Fischer, André; Ehrenreich, Hannelore

doi:10.15252/emmm.201505696

Cited by 42 publications

(49 citation statements)

References 73 publications

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“…It is characterized by positive symptoms, such as delusions and hallucinations, and by negative phenotypes, including impaired cognitive function and social abilities (2,3). A number of genes have been associated with the risk to develop schizophrenia (4)(5)(6). In addition to genetic predisposition, environmental factors, such as urbanicity (7), obstetric complications (8), or exposure to early life stress (ELS) (9,10), are known to increase the risk of developing schizophrenia.…”

Section: Hdac1 Links Early Life Stress To Schizophrenialike Phenotypesmentioning

confidence: 99%

HDAC1 links early life stress to schizophrenia-like phenotypes

Bahari‐Javan

Varbanov

Halder

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

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Section: Hdac1 Links Early Life Stress To Schizophrenialike Phenotypesmentioning

confidence: 99%

HDAC1 links early life stress to schizophrenia-like phenotypes

Bahari‐Javan

Varbanov

Halder

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Genotyping was performed by Affymetrix on a GeneTitan platform. Several quality control steps were applied (SNP call rate > 97%, Fisher's linear discriminant > 3.6, heterozygous cluster strength offset > −0.1, and homozygote ratio offset > −0.9) (Hammer et al , ; Stepniak et al , ). The genotyping results of the GRAS sample have been included in and published as part of the latest PGC study on schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, ).…”

Section: Methodsmentioning

confidence: 99%

A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms

et al. 2017

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Matrix metalloproteinase 9 (MMP‐9) has recently emerged as a molecule that contributes to pathological synaptic plasticity in schizophrenia, but explanation of the underlying mechanisms has been missing. In the present study, we performed a phenotype‐based genetic association study (PGAS) in > 1,000 schizophrenia patients from the Göttingen Research Association for Schizophrenia (GRAS) data collection and found an association between the MMP‐9 rs20544 C/T single‐nucleotide polymorphism (SNP) located in the 3′untranslated region (UTR) and the severity of a chronic delusional syndrome. In cultured neurons, the rs20544 SNP influenced synaptic MMP‐9 activity and the morphology of dendritic spines. We demonstrated that Fragile X mental retardation protein (FMRP) bound the MMP‐9 3′UTR. We also found dramatic changes in RNA structure folding and alterations in the affinity of FMRP for MMP‐9 RNA, depending on the SNP variant. Finally, we observed greater sensitivity to psychosis‐related locomotor hyperactivity in Mmp‐9 heterozygous mice. We propose a novel mechanism that involves MMP‐9‐dependent changes in dendritic spine morphology and the pathophysiology of schizophrenia, providing the first mechanistic insights into the way in which the single base change in the MMP‐9 gene (rs20544) influences gene function and results in phenotypic changes observed in schizophrenia patients.

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“…Prospectively recruited healthy migrants (N = 46; 21.9 ± 4.4 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] years), at the time of immigration to Germany aged 18.7 ± 4.6 years, and N = 821 age-matched non-migrant controls of extended GRAS were analyzed.…”

Section: Nmdar1-ab Seropositivity In Migrants and Age-matched Controlsmentioning

confidence: 99%

Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury

et al. 2020

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Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood–brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.

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Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes

Cited by 42 publications

References 73 publications

HDAC1 links early life stress to schizophrenia-like phenotypes

HDAC1 links early life stress to schizophrenia-like phenotypes

A normal genetic variation modulates synaptic MMP‐9 protein levels and the severity of schizophrenia symptoms

Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury

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