Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine

Nilsson, Simon; Heath, Christopher; Takillah, Samir; Didienne, Steve; Fejgin, Kim; Nielsen, Vibeke; Nielsen, Jacob; Saksida, Lisa M.; Mariani, Jean; Fauré, Philippe; Didriksen, Michael; Robbins, Trevor W.; Bussey, Timothy J.; Mar, Adam

doi:10.1038/s41398-018-0295-3

Cited by 26 publications

(17 citation statements)

References 100 publications

(147 reference statements)

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“…Interestingly, fluctuations of psychotic symptoms in SZ resemble the relapsing remitting pattern of prototypical immunological disorders, suggesting that the peripheral inflammation 5 22qDS+SZ iBBB exhibited substantially impaired barrier integrity, despite the genetic variability introduced by our approach. This phenotype was substantiated in vivo in a 22qDS mouse model harboring a homologous hemizygous deletion (Didriksen et al, 2017;Nilsson et al, 2018;Scarborough et al, 2019). We further interrogated junctional protein expression and immune privilege properties of the BBB in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 85%

“…To evaluate the 22qDS BBB in vivo, we utilized a mouse strain harboring a hemizygous deletion of the 22qDS homologous region on chromosome 16 (Didriksen et al, 2017;Nilsson et al, 2018;Scarborough et al, 2019). These mice mimic much of the biology of 22qDS in humans, including facial deformities and SZ-associated behavioral changes (Didriksen et al, 2017;Nilsson et al, 2018;Scarborough et al, 2019). We assessed BBB integrity by quantifying extravasation of blood proteins into the CNS parenchyma of 22qDS mice and their wild type (WT) littermates.…”

Section: Barrier Function Is Impaired In the 22qds Bbbmentioning

confidence: 99%

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Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

Crockett

Ryan

Vásquez

et al. 2019

Preprint

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Neuroimmune dysregulation is implicated in neuropsychiatric disorders including schizophrenia (SZ).As the blood brain barrier (BBB) is the immunological interface between the brain and the periphery, we investigated whether the BBB is intrinsically compromised in the most common genetic risk factor for SZ, the hemizygous deletion of chromosome 22q11.2 (22qDS). BBB-like endothelium (iBBB) differentiated from human 22qDS+SZ-induced pluripotent stem cells exhibited impaired barrier integrity, a phenotype substantiated in a mouse model of 22qDS. The proinflammatory intercellular adhesion molecule-1 (ICAM-1) was upregulated in 22qDS+SZ iBBB and 22qDS mice, indicating compromise of the BBB immune privilege. This immune imbalance resulted in increased migration/activation of leukocytes crossing the 22qDS+SZ iBBB. Finally, we found heightened astrocyte activation in murine and human 22qDS, suggesting that the BBB promotes astrocyte-mediated neuroinflammation. Overall, the barrier-promoting and immune privilege properties of the 22qDS BBB are compromised, and this might increase the risk for neuropsychiatric disease. 4

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Section: Introductionmentioning

confidence: 85%

Section: Barrier Function Is Impaired In the 22qds Bbbmentioning

confidence: 99%

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

Crockett

Ryan

Vásquez

et al. 2019

Preprint

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“…Another excellent example has been provided by the availability of 22q11.2 chromosomal microdeletion mouse models of the neurocognitive deficits found in human populations, relevant to schizophrenia and attention deficit hyperactivity disorder (ADHD). Given the sensitivity of the attentional deficits to attenuation by amphetamine in ADHD, NEWMEDS collaborations enabled a full neurobiological and behavioural analysis to be made, including the demonstration of a desynchronization of prefrontal-hippocampal oscillations, specific deficits in attentional function and their pharmacological remediation (Nilsson et al 2018 ).…”

Section: Principle 7: Validate the Reproducibility Of Findings By Indmentioning

confidence: 99%

Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology

et al. 2021

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Background There is urgent need for new medications for psychiatric disorders. Mental illness is expected to become the leading cause of disability worldwide by 2030. Yet, the last two decades have seen the pharmaceutical industry withdraw from psychiatric drug discovery after costly late-stage trial failures in which clinical efficacy predicted pre-clinically has not materialised, leading to a crisis in confidence in preclinical psychopharmacology. Methods Based on a review of the relevant literature, we formulated some principles for improving investment in translational neuroscience aimed at psychiatric drug discovery. Results We propose the following 8 principles that could be used, in various combinations, to enhance CNS drug discovery: (1) consider incorporating the NIMH Research Domain Criteria (RDoC) approach; (2) engage the power of translational and systems neuroscience approaches; (3) use disease-relevant experimental perturbations; (4) identify molecular targets via genomic analysis and patient-derived pluripotent stem cells; (5) embrace holistic neuroscience: a partnership with psychoneuroimmunology; (6) use translational measures of neuronal activation; (7) validate the reproducibility of findings by independent collaboration; and (8) learn and reflect. We provide recent examples of promising animal-to-human translation of drug discovery projects and highlight some that present re-purposing opportunities. Conclusions We hope that this review will re-awaken the pharma industry and mental health advocates to the opportunities for improving psychiatric pharmacotherapy and so restore confidence and justify re-investment in the field.

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“…TCP and B12 can now be added to a growing list of drugs and compounds with proven ability to ameliorate the neuronal and/or behavioral deficits found in mouse models of 22q11.2DS (Armando et al, 2020; Fernandez et al, 2019; Mukherjee et al, 2019; Nilsson et al, 2018; Tamura et al, 2016) and, in one case, in patients with 22q11.2DS (Armando et al, 2020). To our knowledge, this study is the first to identify drugs that target TBX1 , the major candidate gene for 22q11.2DS, that have preventative potential in the mouse model.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological rescue of the brain cortex phenotype of Tbx1 mouse mutants: significance for 22q11.2 deletion syndrome

Favicchia

Flore

Lania

et al. 2021

Preprint

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Objectives: Tbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency. Experimental approach: Disease model: Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain. Methods: in situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved. Results: Cortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression. Conclusions: To our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region.

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Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine

Cited by 26 publications

References 100 publications

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

Disruption of the Blood-Brain Barrier in 22q11.2 Deletion Syndrome

Time to re-engage psychiatric drug discovery by strengthening confidence in preclinical psychopharmacology

Pharmacological rescue of the brain cortex phenotype of Tbx1 mouse mutants: significance for 22q11.2 deletion syndrome

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