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Cognition- and circuit-based dysfunction in a mouse model of 22q11.2 microdeletion syndrome: effects of stress

Anushree Tripathi, Michael Spedding, Esther Schenker, Michael Didriksen, Arnaud Cressant, Therese M. Jay
2020 Translational Psychiatry  
Didriksen et al. recently described a novel mouse model (Df(h22q11)/+) with hemizygous deletion of mouse chromosome 16, that corresponds to the region of human 22q11.2 microdeletion 8 .  ... 
doi:10.1038/s41398-020-0687-z pmid:32066701 fatcat:65dnhxk7fjdvjo7o7wnr7344n4

Interactive effects between hemizygous 15q13.3 microdeletion and peripubertal stress on adult behavioral functions

Sandra Giovanoli, Thomas M. Werge, Preben B. Mortensen, Michael Didriksen, Urs Meyer
2018 Neuropsychopharmacology  
8 15q13.3 microdeletion is one of several gene copy number variants (CNVs) conferring increased risk of psychiatric and neurological disorders. This microdeletion gives rise to a variable spectrum of pathological phenotypes, ranging from asymptomatic to severe clinical outcomes. The reasons for these varying phenotypic outcomes remain unknown. Using a mouse model of hemizygous deletion of the orthologous region of 15q13.3, the present study examined whether exposure to stressful life events
more » ... t interact with hemizygous 15q13.3 microdeletion in the development of behavioral dysfunctions. We show that hemizygous 15q13.3 microdeletion alone induces only limited effects on adult behaviors, but when combined with psychological stress in pubescence (postnatal days 30-40), it impairs sensorimotor gating and increases the sensitivity to the psychostimulant drug, amphetamine, at adult age. Stress exposure in adolescence (postnatal days 50-60) did not induce similar interactions with 15q13.3 microdeletion, but led to impaired emotional learning and memory and social behavior regardless of the genetic background. The present study provides the first evidence for interactive effects between hemizygous 15q13.3 microdeletion and exposure to stressful life events, and at the same time, it emphasizes an important influence of the precise timing of postnatal stress exposure in these interactions. Our findings suggest that hemizygous 15q13.3 microdeletion can act as a "disease primer" that increases the carrier's vulnerability to the detrimental effects of peripubertal stress exposure on adult behaviors. Neuropsychopharmacology (2019) 44:703-710; https://doi.Interactive effects between hemizygous 15q13.3 microdeletion and. . . S Giovanoli et al.
doi:10.1038/s41386-018-0189-3 pmid:30188511 fatcat:s4cldzej2ra2xjak4lvcc6l2om

Cognitive Deficits Caused by Late Gestational Disruption of Neurogenesis in Rats: a Preclinical Model of Schizophrenia

Peter Flagstad, Birte Y Glenthøj, Michael Didriksen
2004 Neuropsychopharmacology  
In a preliminary abstract from our laboratory (Didriksen et al, 1999) , it was described that MAM-treated rats had a deficit in this task compared to controls; however, the experiment has now been repeated  ... 
doi:10.1038/sj.npp.1300625 pmid:15578007 fatcat:g6nc4dhbsfgplguiwjmg7am6fm

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

Aaron Gordon, Annika Gronborg-Forsingdal, Ib Vestergaard Klewe, Jacob Nielsen, Michael Didriksen, Thomas Werge, Daniel H Geschwind
2019 bioRxiv   pre-print
Didriksen M, Fejgin K, Nilsson SR, Birknow MR, Grayton HM, Larsen PH et al.  ...  Nat Neurosci 2016; 19(11): A, Jørgensen TN, Olsen L, Werge T, Didriksen M, Nielsen J. Can Animal Models of Copy Number Variants that Predispose to Schizophrenia Elucidate Underlying Biology?  ... 
doi:10.1101/625368 fatcat:mgu45ro5ira3pficrth4my5ooq

Decrease in parvalbumin-expressing neurons in the hippocampus and increased phencyclidine-induced locomotor activity in the rat methylazoxymethanol (MAM) model of schizophrenia

Silke Penschuck, Peter Flagstad, Michael Didriksen, Marcel Leist, Adina T. Michael-Titus
2006 European Journal of Neuroscience  
Treatment of rats with methylazoxymethanol (MAM) on gestational day (GD)17 disrupts corticolimbic development in the offspring (MAM-GD17 rats) and leads to abnormalities in adult MAM-GD17 rats resembling those described in schizophrenic patients. The underlying changes in specific cortical and limbic cell populations remain to be characterised. In schizophrenia, decreases in inhibitory c-aminobutyric acid (GABA)-containing interneurons that express the calcium-binding protein parvalbumin have
more » ... en reported in the prefrontal cortex and hippocampus. In this study we analysed the expression of parvalbumin (PV), calretinin (CR) and calbindin (CB) in the prefrontal cortex and hippocampus of MAM-GD17 rats. Exposure in utero to MAM led to a significant decrease in the number of neurons expressing PV in the hippocampus, but not the prefrontal cortex. Neurons expressing CR or CB were not affected in either structure. The neurochemical changes in MAM-GD17 rats were accompagnied by increased hyperlocomotion after administration of phencyclidine (PCP), analogous to the hypersensitivity of schizophrenic patients to PCP. Therefore, the developmental MAM-GD17 model reproduces key neurochemical and behavioural features that reflect cortical and subcortical dysfunction in schizophrenia, and could be a useful tool in the development of new antipsychotic drugs.
doi:10.1111/j.1460-9568.2005.04536.x pmid:16420437 fatcat:tcuxo5ceczb4ddjzfygajg4lne

The Danish 22q11 research initiative

Henriette Schmock, Anders Vangkilde, Kit Melissa Larsen, Elvira Fischer, Michelle Rosgaard Birknow, Jens Richardt Møllegaard Jepsen, Charlotte Olesen, Flemming Skovby, Kerstin Jessica Plessen, Morten Mørup, Ollie Hulme, William Frans Christiaan Baaré (+4 others)
2015 BMC Psychiatry  
Neurodevelopmental brain disorders such as schizophrenia, autism and attention deficit hyperactivity disorder are complex disorders with heterogeneous etiologies. Schizophrenia and autism are difficult to treat and often cause major individual suffering largely owing to our limited understanding of the disease biology. Thus our understanding of the biological pathogenesis needs to be substantiated to enable development of more targeted treatment options with improved efficacy. Insights into the
more » ... pre-morbid disease dynamics, the morbid condition and the underlying biological disease mechanisms may come from studies of subjects with homogenous etiologies. Breakthroughs in psychiatric genetics have shown that several genetic anomalies predispose for neurodevelopmental brain disorders. We have established a Danish research initiative to study the common microdeletion at chromosome 22q11.2, which is one of the genetic anomalies that confer high risk of schizophrenia, autism and attention deficit hyperactivity disorder. Methods/design: The study applies a "cause-to-outcome" strategy to identify pre-morbid pathogenesis and underlying biological disease mechanisms of psychosis and secondarily the morbid condition of autism and attention deficit hyperactivity disorder. We use a population based epidemiological design to inform on disease prevalence, environmental risk factors and familial disposition for mental health disorders and a case control study design to map the functional effects across behavioral and neurophysiological traits of the 22q11 deletion in a recruited sample of Danish individuals. Discussion: Identification of predictive pre-morbid clinical, cognitive, functional and structural brain alterations in 22q11 deletion carriers may alter current clinical practice from symptomatic therapy of manifest mental illness into early intervention strategies, which may also be applicable to at risk subjects without known etiology. Hopefully new insights into the biological disease mechanisms, which are mandatory for novel drug developments, can improve the outcome of the pharmacological interventions in psychiatry.
doi:10.1186/s12888-015-0594-7 pmid:26384214 pmcid:PMC4574168 fatcat:e4mffyobezhphb62l6tamrcya4

Altered dopaminergic firing pattern and novelty response underlie ADHD-like behavior of SorCS2-deficient mice

Ditte Olsen, Niels Wellner, Mathias Kaas, Inge E. M. de Jong, Florence Sotty, Michael Didriksen, Simon Glerup, Anders Nykjaer
2021 Translational Psychiatry  
AbstractAttention deficit hyperactivity disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder worldwide. Affected individuals present with hyperactivity, inattention, and cognitive deficits and display a characteristic paradoxical response to drugs affecting the dopaminergic system. However, the underlying pathophysiology of ADHD and how this relates to dopaminergic transmission remains to be fully understood. Sorcs2−/− mice uniquely recapitulate symptoms reminiscent of
more » ... HD in humans. Here, we show that lack of SorCS2 in mice results in lower sucrose intake, indicating general reward deficits. Using in-vivo recordings, we further find that dopaminergic transmission in the ventral tegmental area (VTA) is shifted towards a more regular firing pattern with marked reductions in the relative occurrence of irregular firing in Sorcs2−/− mice. This was paralleled by abnormal acute behavioral responses to dopamine receptor agonists, suggesting fundamental differences in dopaminergic circuits and indicating a perturbation in the balance between the activities of the postsynaptic dopamine receptor DRD1 and the presynaptic inhibitory autoreceptor DRD2. Interestingly, the hyperactivity and drug response of Sorcs2−/− mice were markedly affected by novelty. Taken together, our findings show how loss of a candidate ADHD-risk gene has marked effects on dopaminergic circuit function and the behavioral response to the environment.
doi:10.1038/s41398-021-01199-9 pmid:33495438 fatcat:re54t2xc5ff35gh5aqosu73354

Altered auditory processing and effective connectivity in 22q11.2 deletion syndrome

Kit Melissa Larsen, Morten Mørup, Michelle Rosgaard Birknow, Elvira Fischer, Oliver Hulme, Anders Vangkilde, Henriette Schmock, William Frans Christiaan Baaré, Michael Didriksen, Line Olsen, Thomas Werge, Hartwig R. Siebner (+1 others)
2018 Schizophrenia Research  
doi:10.1016/j.schres.2018.01.026 pmid:29395612 fatcat:mdgvzejv25dihm423thc62yzrm

Genome-wide scans using archived neonatal dried blood spot samples

Mads V Hollegaard, Jonas Grauholm, Anders Børglum, Mette Nyegaard, Bent Nørgaard-Pedersen, Torben Ørntoft, Preben B Mortensen, Carsten Wiuf, Ole Mors, Michael Didriksen, Poul Thorsen, David M Hougaard
2009 BMC Genomics  
Identification of disease susceptible genes requires access to DNA from numerous well-characterised subjects. Archived residual dried blood spot samples from national newborn screening programs may provide DNA from entire populations and medical registries the corresponding clinical information. The amount of DNA available in these samples is however rarely sufficient for reliable genome-wide scans, and whole-genome amplification may thus be necessary. This study assess the quality of DNA
more » ... ed from different amplification protocols by evaluating fidelity and robustness of the genotyping of 610,000 single nucleotide polymorphisms, using the Illumina Infinium HD Human610-Quad BeadChip. Whole-genome amplified DNA from 24 neonatal dried blood spot samples stored between 15 to 25 years was tested, and high-quality genomic DNA from 8 of the same individuals was used as reference. Results: Using 3.2 mm disks from dried blood spot samples the optimal DNA-extraction and amplification protocol resulted in call-rates between 99.15% -99.73% (mean 99.56%, N = 16), and conflicts with reference DNA in only three per 10,000 genotype calls. Conclusion: Whole-genome amplified DNA from archived neonatal dried blood spot samples can be used for reliable genome-wide scans and is a cost-efficient alternative to collecting new samples.
doi:10.1186/1471-2164-10-297 pmid:19575812 pmcid:PMC2713266 fatcat:st5tlpd2yrfwfoxnz5j4p42haa

22q11.2 Deletion Syndrome Is Associated With Impaired Auditory Steady-State Gamma Response

Kit Melissa Larsen, Giovanni Pellegrino, Michelle Rosgaard Birknow, Trine Nørgaard Kjær, William Frans Christiaan Baaré, Michael Didriksen, Line Olsen, Thomas Werge, Morten Mørup, Hartwig Roman Siebner
2017 Schizophrenia Bulletin  
The 22q11.2 deletion syndrome confers a markedly increased risk for schizophrenia. 22q11.2 deletion carriers without manifest psychotic disorder offer the possibility to identify functional abnormalities that precede clinical onset. Since schizophrenia is associated with a reduced cortical gamma response to auditory stimulation at 40 Hz, we hypothesized that the 40 Hz auditory steady-state response (ASSR) may be attenuated in nonpsychotic individuals with a 22q11.2 deletion. Methods: Eighteen
more » ... ung nonpsychotic 22q11.2 deletion carriers and a control group of 27 noncarriers with comparable age range (12-25 years) and sex ratio underwent 128-channel EEG. We recorded the cortical ASSR to a 40 Hz train of clicks, given either at a regular inter-stimulus interval of 25 ms or at irregular intervals jittered between 11 and 37 ms. Results: Healthy noncarriers expressed a stable ASSR to regular but not in the irregular 40 Hz click stimulation. Both gamma power and inter-trial phase coherence of the ASSR were markedly reduced in the 22q11.2 deletion group. The ability to phase lock cortical gamma activity to regular auditory 40 Hz stimulation correlated with the individual expression of negative symptoms in deletion carriers (ρ = −0.487, P = .041). Conclusions: Nonpsychotic 22q11.2 deletion carriers lack efficient phase locking of evoked gamma activity to regular 40 Hz auditory stimulation. This abnormality indicates a dysfunction of fast intracortical oscillatory processing in the gamma-band. Since ASSR was attenuated in nonpsychotic deletion carriers, ASSR deficiency may constitute a premorbid risk marker of schizophrenia.
doi:10.1093/schbul/sbx058 pmid:28521049 pmcid:PMC5815132 fatcat:ysz6egf24zb2lc4jlkm5upsqei

Individuals with 22q11.2 deletion syndrome show intact prediction but reduced adaptation in responses to repeated sounds: evidence from Bayesian mapping [article]

Kit Melissa Larsen, Morten Moerup, Michelle Birknow, Elvira Fischer, Line Olsen, Michael Didriksen, William Frans Christiaan Baare, Thomas Werge, Marta Isabel Garrido, Hartwig Roman Siebner
2018 bioRxiv   pre-print
One of the most common copy number variants, the 22q11.2 microdeletion, confers a increased risk for schizophrenia. Since schizophrenia has been associated with an aberrant neural response to repeated stimuli through both reduced adaptation and prediction, we here hypothesized that this may also be the case in nonpsychotic individuals with a 22q11.2 deletion. Methods: We recorded high-density EEG from 19 individuals with 22q11.2 deletion syndrome (12-25 years), as well as 27 healthy volunteers
more » ... ith comparable age and sex distribution, while they listened to a sequence of sounds arranged in a roving oddball paradigm. Using posterior probability maps and dynamic causal modelling we tested three different models accounting for repetition dependent changes in cortical responses as well as in effective connectivity; namely an adaptation model, a prediction model, and a model including both adaptation and prediction. Results: Repetition-dependent changes were parametrically modulated by a combination of adaptation and prediction and were apparent in both cortical responses and in the underlying effective connectivity. This effect was reduced in individuals with a 22q11.2 deletion and was negatively correlated with negative symptom severity. Follow-up analysis showed that the reduced effect of the combined adaptation and prediction model seen in individuals with 22q11.2 deletion was driven by reduced adaptation rather than prediction failure. Conclusions: Our findings suggest that adaptation is reduced in individuals with a 22q11.2 deletion, which can be interpreted in light of the framework of predictive coding as a failure to suppress prediction errors.
doi:10.1101/441634 fatcat:rj6wsbsrvne2zikl3gj2faqpfu

Glucocorticoid Receptor and Myocyte Enhancer Factor 2 Cooperate to Regulate the Expression of c-JUN in a Neuronal Context

Niels Speksnijder, Kenneth V. Christensen, Michael Didriksen, E. Ronald De Kloet, Nicole A. Datson
2012 Journal of Molecular Neuroscience  
The glucocorticoid receptor (GR) and myocyte enhancer factor 2 (MEF2
doi:10.1007/s12031-012-9809-2 pmid:22622902 pmcid:PMC3413818 fatcat:pcx45oamjjeytexxwb5iq2e5lq

Disruption of Neurogenesis on Gestational Day 17 in the Rat Causes Behavioral Changes Relevant to Positive and Negative Schizophrenia Symptoms and Alters Amphetamine-Induced Dopamine Release in Nucleus Accumbens

Peter Flagstad, Arne Mørk, Birte Y Glenthøj, Johan van Beek, Adina T Michael-Titus, Michael Didriksen
2004 Neuropsychopharmacology  
own preliminary behavioral studies comparing MAM treatment on GD9 to GD17 of gestation also suggested that GD17 MAM treatment (and to some extent GD15 MAM treatment) induced cognitive changes in rats (Didriksen  ... 
doi:10.1038/sj.npp.1300516 pmid:15199377 fatcat:sbksxc6xmndmjggtwed5um27be

Association of Proton Pump Inhibitor and Histamine H2-Receptor Antagonists with Restless Legs Syndrome

Eric J Earley, Maria Didriksen, Bryan R Spencer, Joseph E Kiss, Christian Erikstrup, Ole B Pedersen, Erik Sørensen, Kristoffer S Burgdorf, Steven H Kleinman, Alan E Mast, Michael P Busch, Henrik Ullum (+1 others)
2020 Sleep  
Restless Legs Syndrome (RLS) is a common sensorimotor disorder, which can disrupt sleep and is thought to be caused in part by low cellular iron stores. Proton pump inhibitors (PPI) and histamine H2-receptor antagonists (H2A) are among the most commonly used drugs worldwide and show evidence of causing iron deficiency. We conducted a case/non-case observational study of blood donors in the U.S. (N=13,403; REDS-III) and Denmark (N=50,323; Danish Blood Donor Study, DBDS), both of which had
more » ... e blood count measures and a completed RLS assessment via the Cambridge Hopkins RLS questionnaire (CH-RLSq). After adjusting for age, sex, race, BMI, blood donation frequency, smoking, hormone use, and iron supplement use, PPI/H2A use was associated with RLS (Odds Ratio [OR] = 1.41; 95% confidence interval [CI], 1.13-1.76; P=0.002) in REDS-III for both PPI (OR = 1.43; CI, 1.03 - 1.95; P = 0.03) and H2A (OR = 1.56; CI, 1.10 - 2.16; P = 0.01). DBDS exhibited a similar association with PPIs/H2As (OR = 1.29; CI, 1.20 - 1.40; P < 0.001), and for PPIs alone (OR = 1.27; CI, 1.17-1.38; P < 0.001), but not H2As alone (OR = 1.18; CI, 0.92-1.53; P = 0.2). We found no evidence of blood iron stores mediating this association. The association of PPI, and possibly H2A, consumption with RLS independent of blood iron status and other factors which contribute to RLS risk suggest the need to re-evaluate use of PPI/H2A in populations at particular risk for RLS.
doi:10.1093/sleep/zsaa220 pmid:33119070 pmcid:PMC8033459 fatcat:pvey6y4apbgrrmlvdlyqszszu4

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

Simon R. O. Nilsson, Christopher J. Heath, Samir Takillah, Steve Didienne, Kim Fejgin, Vibeke Nielsen, Jacob Nielsen, Lisa M. Saksida, Jean Mariani, Philippe Faure, Michael Didriksen, Trevor W. Robbins (+2 others)
2018 Translational Psychiatry  
The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to
more » ... wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d'). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0-1.0 mg/kg, i.p.) dose-dependently improved d' in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d' impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.
doi:10.1038/s41398-018-0295-3 pmid:30429456 pmcid:PMC6235862 fatcat:7tsrkt4vzrdzrnche5a732fatq
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