Can Animal Models of Copy Number Variants That Predispose to Schizophrenia Elucidate Underlying Biology?

Forsingdal, Annika; Jørgensen, Trine N.; Olsen, Line; Werge, Thomas; Didriksen, Michael; Nielsen, Jacob

doi:10.1016/j.biopsych.2018.07.004

Cited by 36 publications

(35 citation statements)

References 114 publications

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“…At the same time, the relation between the CNV and potential human disease-related phenotypes in these models, so called "face validity," is of interest 10 . As previously shown, there is little similarity between the disease relevant behaviors in the three mouse models studied 9 . This is consistent with the individuals carrying these CNVs 64 , as well as the gene expression patterns observed in this study.…”

Section: Face Validitymentioning

confidence: 80%

“…Published studies indicate that between 2.5 to 5% of SCZ patients carry one of the eight CNVs most frequently associated with SCZ 2 . These CNVs have relatively high penetrance compared with common variants and have clearly defined and evolutionary conserved genomic structure 2,9 , which makes them well suited for generating mouse models to study the brain mechanisms underlying neuropsychiatric disease risk [9][10][11] . Additionally, all of these CNVs have pleotropic effects, variably increasing risk for a range of neurodevelopmental outcomes, including intellectual disability (ID), autism spectrum disorder (ASD) and SCZ.…”

Section: Introductionmentioning

confidence: 99%

“…To address whether specific genetic variants imparting major risk for schizophrenia or ASD converge at the molecular level, we leveraged three previously published mouse models with CNVs carrying significant risk for these disorders, Df(h15q13)/+ [13][14][15] , Df(h22q11)/+ 16 , and Df(h1q21)/+ 17 , which harbor the 15q13.3 deletion 18 , 22q11.2 deletion 19 , and 1q21.1 deletion 2 respectively. These three models have strong construct validity as they all harbor deletions of regions homologous to those found in human deletions associated with SCZ and ASD 2,9,19 . Of note, these mice were tested for face validity with respect to phenotypic aspects of SCZ and ASD.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations

Gordon

Grønborg-Forsingdal

Klewe

et al. 2019

Preprint

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Genetic risk for psychiatric illness is complex, so identification of shared molecular pathways where distinct forms of genetic risk might coincide is of substantial interest. A growing body of genetic and genomic studies suggest that such shared molecular pathways exist across disorders with different clinical presentations, such as schizophrenia and autism spectrum disorder (ASD).But how this relates to specific genetic risk factors is unknown. Further, whether some of the molecular changes identified in brain relate to potentially confounding antemortem or postmortem factors is difficult to prove. We analyzed the transcriptome from the cortex and hippocampus of three mouse lines modeling human copy number variants (CNVs) associated with schizophrenia and ASD: Df(h15q13)/+, Df(h22q11)/+, and Df(h1q21)/+ which carry the 15q13.3 deletion, 22q11.2 deletion, and 1q21.1 deletion, respectively. Although we found very little overlap of differential expression at the level of individual genes, gene network analysis identified two modules of co-expressed genes that were dysregulated across all three mouse models. One module observed in both cortex and hippocampus was associated with neuronal energetics and firing rate, and overlapped with changes identified in post mortem human brain from SCZ and ASD patients. These data highlight aspects of convergent gene expression in mouse models harboring major risk alleles, and strengthen the connection between neuronal energetic dysfunction and neuropsychiatric disorders in humans. Methods SamplesMice were bred and housed until 8 weeks by Taconic MB (Lille Skensved, Denmark), and then transported to the Lundbeck animal facility. Detailed description of animal housing and handling has been previously described 15 . Adult mice (>10 weeks old) harboring the CNV as well control littermates were sacrificed by cervical dislocation and parietal cortex or hippocampus were dissected by hand and stored at -80°C. With the exception of Df(h15q13)-/-the cortex and hippocampus were dissected from separate animals. All studies were carried out in accordance with Danish legislation, granted by the animal welfare committee, appointed by the Danish Ministry of Food, Agriculture and Fisheries-Danish Veterinary and Food Administration. Samples were lysed and homogenized in RA1 lysis buffer with 1% β-mercaptoethanol (Macherey-Nagel,

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Section: Face Validitymentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations

Gordon

Grønborg-Forsingdal

Klewe

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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“…To date, there is no published data directly exploring the differences in phenotypic presentations between SCZ patients with known syndromic CNVs and those without. Forsingdal et al (2018) evaluated SCZ-related phenotypes in mouse models harboring SCZ-associated CNVs, and reported that 1q21 deletion mice show altered dopaminergic transmission and response to psychostimulants, both of which are postulated to worsen positive SCZ symptoms (e.g. hallucinations).…”

Section: Discussionmentioning

confidence: 99%

“…hallucinations). Microdeletion 22q11.2 mice were also found to show heightened response to NMDA antagonists, hinting at molecular disturbances relevant to positive symptoms in SCZ (Forsingdal et al, 2018). These and our study results highlight the potential impact of CNVs on modulating symptom presentation and severity in SCZ.…”

Section: Discussionmentioning

confidence: 99%

Copy number variant syndromes are frequent in schizophrenia: progressing towards a CNV-schizophrenia model

Sriretnakumar

Zai

Wasim

et al. 2019

Preprint

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The genetic underpinnings of schizophrenia (SCZ) remain unclear. SCZ genetic studies thus far have only identified numerous single nucleotide polymorphisms with small effect sizes and a handful of copy number variants (CNVs). This study investigates the prevalence of well-characterized CNV syndromes and candidate CNVs within a cohort of 348 SCZ patients, and explores correlations to their phenotypic findings. There was an enrichment of syndromic CNVs in the cohort, as well as brain-related and immune pathway genes within the detected CNVs. SCZ patients with brain-related CNVs had increased CNV burden, neurodevelopmental features, and types of hallucinations. Based on these results, we propose a CNV-SCZ model wherein specific phenotypic profiles should be prioritized for CNV screening within the SCZ patient population.

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Antipsychotic Agents

Ablordeppey

Ofori

2021

Burger's Medicinal Chemistry and Drug Discovery

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Schizophrenia is one of the most severe diseases of the brain and is characterized by a spectrum of symptoms including positive, negative, and cognitive symptoms. Even though schizophrenia has a low worldwide prevalence (0.4–0.7%), it is one of the most devastating diseases of the central nervous system (CNS). Despite the immense studies on schizophrenia over the years, the exact cause of the disorder remains unknown. Therefore, morbidity studies and their outcomes for schizophrenia continue to rely on descriptive definitions spelled out in the Diagnostic and Statistical Manual of Mental Disorders‐fifth edition (DSM‐5). Current pharmacotherapy of the disease involves the use of antipsychotic agents that target CNS receptors including dopamine and serotonin receptor subtypes. Despite the success in the management of psychiatric illness most of the current antipsychotics are saddled with problems such as inefficacy across patient populations and disease domains and intolerable side effects that limit their widespread utility. Evolving paradigm shift in antipsychotic drug discovery efforts over the last decade has begun to address these issues opening the door for new hypotheses that integrate well‐known neurotransmitter systems with neuronal circuits. Recent advances in molecular biology and genetics are also paving the way for a better understanding of the etiology and pathophysiology of schizophrenia. In addition to reviewing currently used agents, this article will focus on the advances made to address the stated problems and highlight the paradigm shift in the antipsychotic drug discovery area.

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Can Animal Models of Copy Number Variants That Predispose to Schizophrenia Elucidate Underlying Biology?

Cited by 36 publications

References 114 publications

Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations

Transcriptomic networks implicate neuronal energetic abnormalities in three mouse models harboring autism and schizophrenia-associated mutations

Copy number variant syndromes are frequent in schizophrenia: progressing towards a CNV-schizophrenia model

Antipsychotic Agents

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