Publications by authors named "Martien J H Kas"

71 Publications

Social withdrawal: An initially adaptive behavior that becomes maladaptive when expressed excessively.

Neurosci Biobehav Rev 2020 09 28;116:251-267. Epub 2020 Jun 28.

Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, the Netherlands. Electronic address:

Social withdrawal is found across neuropsychiatric disorders and in numerous animal species under various conditions. It has substantial impact on the quality of life in patients suffering from neuropsychiatric disorders. Often it occurs prodromal to the disease, suggesting that it is either an early biomarker or central to its etiology. Healthy social functioning is supported by the social brain of which the building blocks go back millions of years, showing overlap between humans, rodents and insects. Thus, to elucidate social withdrawal, we have to approach its environmental triggers and its neural and molecular genetic determinants in an evolutionary context. Pathological social withdrawal may originate from a faulty regulation of specific neural circuits. As there is considerable heritability in social disorders, the genetic building blocks of the social decision making network might be our most relevant target to obtain an understanding of the transition of normal social interaction into social withdrawal.
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http://dx.doi.org/10.1016/j.neubiorev.2020.06.030DOI Listing
September 2020

Cross-site Reproducibility of Social Deficits in Group-housed BTBR Mice Using Automated Longitudinal Behavioural Monitoring.

Neuroscience 2020 10 5;445:95-108. Epub 2020 May 5.

Groningen Institute for Evolutionary Life Sciences, University of Groningen, Groningen, The Netherlands. Electronic address:

Social withdrawal is associated with a variety of neuropsychiatric disorders, including neurodevelopmental disorders. Rodent studies provide the opportunity to study neurobiological mechanisms underlying social withdrawal, however, homologous paradigms to increase translatability of social behaviour between human and animal observation are needed. Standard behavioural rodent assays have limited ethological validity in terms of number of interaction partners, type of behaviour, duration of observation and environmental conditions. In addition, reproducibility of behavioural findings in rodents is further limited by manual and subjective behavioural scoring. Using a newly developed automated tracking tool for longitudinal monitoring of freely moving mice, we assessed social behaviours (approach, sniff, follow and leave) over seven consecutive days in colonies of BTBR and of C57BL/6J mice in two independent laboratories. Results from both laboratories confirmed previous findings of reduced social interaction in BTBR mice revealing a high level of reproducibility for this mouse phenotype using longitudinal colony assessments. In addition, we showed that detector settings contribute to laboratory specific findings as part of the behavioural data analysis procedure. Our cross-site study demonstrates reproducibility and robustness of reduced social interaction in BTBR mice using automated analysis in an ethologically relevant context.
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http://dx.doi.org/10.1016/j.neuroscience.2020.04.045DOI Listing
October 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Nat Genet 2019 08 15;51(8):1207-1214. Epub 2019 Jul 15.

Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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http://dx.doi.org/10.1038/s41588-019-0439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779477PMC
August 2019

RFID-supported video tracking for automated analysis of social behaviour in groups of mice.

J Neurosci Methods 2019 09 27;325:108323. Epub 2019 Jun 27.

Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Riss, Germany.

Background: Deficits in social behaviour, e.g. social withdrawal, appear as an early sign of many neuropsychiatric disorders. Investigation of the biological basis of social withdrawal and development of new targets for treatment requires reliable quantification methods of social behaviour.

New Method: In order to study behavioural deficits in preclinical rodent models, we developed a tracking and analysis tool for behavioural observations in groups of mice. RFID-Assisted SocialScan is based on video tracking supported by radio-frequency identification (RFID). For this purpose, mice were labelled with RFID tags providing unique animal identity and location in the arena. An integrated software package enables automatic detection of predefined behavioural events, which are extracted from video recordings. We designed a social arena that can be flexibly adapted for various behavioural experiments.

Results: We demonstrate the utility of our newly developed tracking tool by monitoring colonies of C57BL/6 J mice. We assessed social (approach, contact, follow, leave) and locomotor activities over multiple days.

Comparison With Other Existing Methods: RFID-Assisted SocialScan is an automated tracking and analysis tool for long-term behavioural observations of multiple freely moving mice housed in ethologically relevant environment.

Conclusions: Here, we demonstrate the performance of a newly developed behavioural tracking system that can be used for long-term translational studies of social behaviour in groups of freely moving mice.
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http://dx.doi.org/10.1016/j.jneumeth.2019.108323DOI Listing
September 2019

Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice.

Eur Neuropsychopharmacol 2019 01 15;29(1):16-31. Epub 2018 Dec 15.

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands; Groningen Institute for Evolutionary Life Sciences, University of Groningen, The Netherlands. Electronic address:

Polyunsaturated fatty acids (PUFAs) are one of the main cellular building blocks, and dietary changes in PUFA composition are proposed as a potential route to influence brain development. For example, initial studies indicated that there is a relation between blood omega-6(n-6)/omega-3(n-3) PUFA ratios and neurodevelopmental disease diagnosis. To study the consequences of dietary n-6/n-3 PUFA ratio changes, we investigated the impact of a n-3 supplemented and n-3 deficient diet in developing BTBR T + Itpr3tf/J (BTBR) - a mouse inbred strain displaying Autism Spectrum Disorder (ASD)-like symptomatology - and control C57BL/6J mice. This study showed that pre- and postnatal changed dietary n-6/n-3 ratio intake has a major impact on blood and brain PUFA composition, and led to delayed physical development and puberty onset in both strains. The PUFA induced developmental delay did not impact adult cognitive performance, but resulted in reduced social interest, a main ASD behavioral feature. Thus, both chronic dietary n-3 PUFA supplementation and depletion may not be beneficial.
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http://dx.doi.org/10.1016/j.euroneuro.2018.11.1106DOI Listing
January 2019

Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice.

Mol Autism 2018 13;9:63. Epub 2018 Dec 13.

5Groningen Institute for Evolutionary Life Sciences, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands.

Background: Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds.

Methods: We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD.

Results: Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations.

Conclusions: These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds.
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http://dx.doi.org/10.1186/s13229-018-0252-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293525PMC
January 2019

New approaches in psychiatric drug development.

Eur Neuropsychopharmacol 2018 09 25;28(9):983-993. Epub 2018 Jul 25.

Faculty of Science and Engineering, Groningen Institute for Evolutionary Life Sciences, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. Electronic address:

Numerous novel neuroscience-based drug targets have been identified in recent years. However, it remains unclear how these targets relate to the expression of symptoms in central nervous system (CNS) disorders in general and psychiatric disorders in particular. To discuss this issue, a New Frontiers Meetings of European College of Neuropsychopharmacology (ECNP) was organized to address the challenges in translational neuroscience research that are impeding the effective development of new treatments. The main aim of this meeting was to discuss scientific insights, concepts and methodologies in order to improve drug development for psychiatric disorders. The meeting was designed to bring together stakeholders from academia, pharmaceutical industry, and regulatory agencies. Here we provide a synopsis of the proceedings from the meeting entitled 'New approaches to psychiatric drug development'. New views on psychiatric drug development were presented to address the challenges and pitfalls as identified by the different stakeholders. The general conclusion of the meeting was that drug discovery could be stimulated by designing new classification and sensitive assessment tools for psychiatric disorders, which bear closer relationships to neuropharmacological and neuroscientific developments. This is in line with the vision of precision psychiatry in which patients are clustered, not merely on symptoms, but primarily on biological phenotypes that represent pathophysiological relevant and 'drugable' processes. To achieve these goals, a closer collaboration between all stakeholders in early stages of development is essential to define the research criteria together and to reach consensus on new quantitative biological methodologies and etiology-directed treatments.
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http://dx.doi.org/10.1016/j.euroneuro.2018.06.006DOI Listing
September 2018

Heterogeneity of Cell Surface Glutamate and GABA Receptor Expression in Shank and CNTN4 Autism Mouse Models.

Front Mol Neurosci 2018 19;11:212. Epub 2018 Jun 19.

Institute for Anatomy and Cell Biology, Ulm University, Ulm, Germany.

Autism spectrum disorder (ASD) refers to a large set of neurodevelopmental disorders, which have in common both repetitive behavior and abnormalities in social interactions and communication. Interestingly, most forms of ASD have a strong genetic contribution. However, the molecular underpinnings of this disorder remain elusive. The gene (and to a lesser degree ) which encode for the postsynaptic density (PSD) proteins SHANK3/SHANK2 and the gene which encodes for the neuronal glycoprotein CONTACTIN4 (CNTN4) exhibit mutated variants which are associated with ASD. Like many of the other genes associated with ASD, both and affect synapse formation and function and are therefore related to the proper development and signaling capability of excitatory and inhibitory neuronal networks in the adult mammal brain. In this study, we used mutant/knock-out mice of Shank2 (), Shank3 (αβ), and Cntn4 () as ASD-models to explore whether these mice share a molecular signature in glutamatergic and GABAergic synaptic transmission in ASD-related brain regions. Using a biotinylation assay and subsequent western blotting we focused our analysis on cell surface expression of several ionotropic glutamate and GABA receptor subunits: GluA1, GluA2, and GluN1 were analyzed for excitatory synaptic transmission, and the α1 subunit of the GABA receptor was analyzed for inhibitory synaptic transmission. We found that both and αβ mice exhibit reduced levels of several cell surface glutamate receptors in the analyzed brain regions-especially in the striatum and thalamus-when compared to wildtype controls. Interestingly, even though mice also show reduced levels of some cell surface glutamate receptors in the cortex and hippocampus, increased levels of cell surface glutamate receptors were found in the striatum. Moreover, mice do not only show brain region-specific alterations in cell surface glutamate receptors but also a downregulation of cell surface GABA receptors in several of the analyzed brain regions. The results of this study suggest that even though mutations in defined genes can be associated with ASD this does not necessarily result in a common molecular phenotype in surface expression of glutamatergic and GABAergic receptor subunits in defined brain regions.
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http://dx.doi.org/10.3389/fnmol.2018.00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018460PMC
June 2018

Multisensory cortical processing and dysfunction across the neuropsychiatric spectrum.

Neurosci Biobehav Rev 2019 02 26;97:138-151. Epub 2018 Feb 26.

Groningen Institute for Evolutionary Life Sciences, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands. Electronic address:

Sensory processing is affected in multiple neuropsychiatric disorders like schizophrenia and autism spectrum disorders. Genetic and environmental factors guide the formation and fine-tuning of brain circuitry necessary to receive, organize, and respond to sensory input in order to behave in a meaningful and consistent manner. During certain developmental stages the brain is sensitive to intrinsic and external factors. For example, disturbed expression levels of certain risk genes during critical neurodevelopmental periods may lead to exaggerated brain plasticity processes within the sensory circuits, and sensory stimulation immediately after birth contributes to fine-tuning of these circuits. Here, the neurodevelopmental trajectory of sensory circuit development will be described and related to some example risk gene mutations that are found in neuropsychiatric disorders. Subsequently, the flow of sensory information through these circuits and the relationship to synaptic plasticity will be described. Research focusing on the combined analyses of neural circuit development and functioning are necessary to expand our understanding of sensory processing and behavioral deficits that are relevant across the neuropsychiatric spectrum.
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http://dx.doi.org/10.1016/j.neubiorev.2018.02.010DOI Listing
February 2019

The Visible Burrow System: A behavioral paradigm to assess sociability and social withdrawal in BTBR and C57BL/6J mice strains.

Behav Brain Res 2018 05 7;344:9-19. Epub 2018 Feb 7.

Groningen Institute for Evolutionary Life Science, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands. Electronic address:

Disrupted sociability and consequent social withdrawal are (early) symptoms of a wide variety of neuropsychiatric diseases, such as schizophrenia, autism spectrum disorders, depressive disorders and Alzheimer's disease. The paucity of objective measures to translationally assess social withdrawal characteristics has been an important limitation to study this behavioral phenotype, both in human and rodents. The aim of the present study was to investigate sociability and social withdrawal in rodents using an ethologically valid behavioral paradigm, the Visible Burrow System (VBS). The VBS mimics a natural environment, with male and female rodents housed together in an enclosure where a large open arena is connected to a continuously dark burrow system that includes 4 nest boxes. In this study, mixed-sex colonies of C57BL/6J and of BTBR mice have been investigated (n = 8 mice per colony). Results showed marked differences between the two strains, in terms of sociability as well as social withdrawal behaviors. In particular, BTBR mice performed less social behaviors and have a preference for non-social behaviors compared to C57BL/6J mice. Neurobiologically, the decreased sociability of BTBR was accompanied by reduced GABA and increased glutamate concentrations in brain prefrontal cortex (PFC) and amygdala regions. In conclusion, our study validated the use of the VBS as an ethologically relevant behavioral paradigm in group-housed mice to investigate individual sociability and social withdrawal features and their underlying neurobiology. This paradigm may provide new insights to develop new therapeutic treatments for behavioral dysfunctions that may be relevant across neuropsychiatric diseases.
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http://dx.doi.org/10.1016/j.bbr.2018.02.003DOI Listing
May 2018

Loss of Cntnap2 Causes Axonal Excitability Deficits, Developmental Delay in Cortical Myelination, and Abnormal Stereotyped Motor Behavior.

Cereb Cortex 2019 02;29(2):586-597

Instituto de Neurociencias, Consejo Superior de Investigaciones Científicas & Universidad Miguel Hernández, Sant Joan d'Alacant, Spain.

Contactin-associated protein-like 2 (Caspr2) is found at the nodes of Ranvier and has been associated with physiological properties of white matter conductivity. Genetic variation in CNTNAP2, the gene encoding Caspr2, has been linked to several neurodevelopmental conditions, yet pathophysiological effects of CNTNAP2 mutations on axonal physiology and brain myelination are unknown. Here, we have investigated mouse mutants for Cntnap2 and found profound deficiencies in the clustering of Kv1-family potassium channels in the juxtaparanodes of brain myelinated axons. These deficits are associated with a change in the waveform of axonal action potentials and increases in postsynaptic excitatory responses. We also observed that the normal process of myelination is delayed in Cntnap2 mutant mice. This later phenotype is a likely modulator of the developmental expressivity of the stereotyped motor behaviors that characterize Cntnap2 mutant mice. Altogether, our results reveal a mechanism linked to white matter conductivity through which mutation of CNTNAP2 may affect neurodevelopmental outcomes.
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http://dx.doi.org/10.1093/cercor/bhx341DOI Listing
February 2019

Structural abnormalities in the primary somatosensory cortex and a normal behavioral profile in Contactin-5 deficient mice.

Cell Adh Migr 2018 01 27;12(1):5-18. Epub 2017 Mar 27.

a Department of Translational Neuroscience , Brain Centre Rudolf Magnus, University Medical Centre Utrecht , Utrecht , the Netherlands.

Contactin-5 (Cntn5) is an immunoglobulin cell adhesion molecule that is exclusively expressed in the central nervous system. In view of its association with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), this study focused on Cntn5-positive areas in the forebrain and aimed to explore the morphological and behavioral phenotypes of the Cntn5 null mutant (Cntn5) mouse in relation to these areas and ASD symptomatology. A newly generated antibody enabled us to elaborately describe the spatial expression pattern of Cntn5 in P7 wild type (Cntn5) mice. The Cntn5 expression pattern included strong expression in the cerebral cortex, hippocampus and mammillary bodies in addition to described previously brain nuclei of the auditory pathway and the dorsal thalamus. Thinning of the primary somatosensory (S1) cortex was found in Cntn5 mice and ascribed to a misplacement of Cntn5-ablated cells. This phenotype was accompanied by a reduction in the barrel/septa ratio of the S1 barrel field. The structure and morphology of the hippocampus was intact in Cntn5 mice. A set of behavioral experiments including social, exploratory and repetitive behaviors showed that these were unaffected in Cntn5 mice. Taken together, these data demonstrate a selective role of Cntn5 in development of the cerebral cortex without overt behavioral phenotypes.
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http://dx.doi.org/10.1080/19336918.2017.1288788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810773PMC
January 2018

Mapping of a FEB3 homologous febrile seizure locus on mouse chromosome 2 containing candidate genes Scn1a and Scn3a.

Eur J Neurosci 2016 12;44(11):2950-2957

Brain Center Rudolf Magnus, Department of Translational Neuroscience, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.

Febrile seizures (FS) are the most common seizure type in children. Recurrent FS are a risk factor for developing temporal lobe epilepsy later in life and are known to have a strong genetic component. Experimental FS (eFS) can be elicited in mice by warm-air induced hyperthermia. We used this model to screen the chromosome substitution strain (CSS) panel derived from C57BL/6J and A/J for FS susceptibility and identified C57BL/6J-Chr2 /NaJ (CSS2), as the strain with the strongest FS susceptibility phenotype. The aim of this study was to map FS susceptibility loci and select candidate genes on mouse chromosome 2. We generated an F population by intercrossing the hybrids (F ) that were derived from CSS2 and C57BL/6J mice. All CSS2-F individuals were genotyped and phenotyped for eFS susceptibility, and QTL analysis was performed. Candidate gene selection was based on bioinformatics analyses and differential brain expression between CSS2 and C57BL/6J strains determined by microarray analysis. Genetic mapping of the eFS susceptibility trait identified two significant loci: FS-QTL2a (LOD-score 3.6) and FS-QTL2b (LOD-score 6.2). FS-QTL2a contained 44 genes expressed in the brain at post natal day 14. Four of these (Arl6ip6, Cytip, Fmnl2 Ifih1) contained a non-synonymous SNP comparing CSS2 and C57BL/6J, six genes (March7, Nr4a2, Gpd2, Grb14, Scn1a, Scn3a) were differentially expressed between these strains. A region within FS-QTL2a is homologous to the human FEB3 locus. The fact that we identify mouse FS-QTL2a with high FEB3 homology is strong support for the validity of the eFS mouse model to study genetics of human FS.
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http://dx.doi.org/10.1111/ejn.13420DOI Listing
December 2016

Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice.

J Neurodev Disord 2016 2;8. Epub 2016 Mar 2.

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages.

Methods: C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors.

Results: Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice.

Conclusions: Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance.
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http://dx.doi.org/10.1186/s11689-016-9140-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782374PMC
March 2016

mTOR plays an important role in cow's milk allergy-associated behavioral and immunological deficits.

Neuropharmacology 2015 Oct 29;97:220-32. Epub 2015 May 29.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. Electronic address:

Autism spectrum disorder (ASD) is multifactorial, with both genetic as well as environmental factors working in concert to develop the autistic phenotype. Immunological disturbances in autistic individuals have been reported and a role for food allergy has been suggested in ASD. Single gene mutations in mammalian target of rapamycin (mTOR) signaling pathway are associated with the development of ASD and enhanced mTOR signaling plays a central role in directing immune responses towards allergy as well. Therefore, the mTOR pathway may be a pivotal link between the immune disturbances and behavioral deficits observed in ASD. In this study it was investigated whether the mTOR pathway plays a role in food allergy-induced behavioral and immunological deficits. Mice were orally sensitized and challenged with whey protein. Meanwhile, cow's milk allergic (CMA) mice received daily treatment of rapamycin. The validity of the CMA model was confirmed by showing increased allergic immune responses. CMA mice showed reduced social interaction and increased repetitive self-grooming behavior. Enhanced mTORC1 activity was found in the brain and ileum of CMA mice. Inhibition of mTORC1 activity by rapamycin improved the behavioral and immunological deficits of CMA mice. This effect was associated with increase of Treg associated transcription factors in the ileum of CMA mice. These findings indicate that mTOR activation may be central to both the intestinal, immunological, and psychiatric ASD-like symptoms seen in CMA mice. It remains to be investigated whether mTOR can be seen as a therapeutic target in cow's milk allergic children suffering from ASD-like symptoms.
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http://dx.doi.org/10.1016/j.neuropharm.2015.04.035DOI Listing
October 2015

Identification of Srp9 as a febrile seizure susceptibility gene.

Ann Clin Transl Neurol 2014 Apr 12;1(4):239-50. Epub 2014 Mar 12.

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht Utrecht, The Netherlands.

Objective: Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans.

Methods: We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients.

Results: Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE.

Interpretation: Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE.
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http://dx.doi.org/10.1002/acn3.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292741PMC
April 2014

Autistic-like behavioural and neurochemical changes in a mouse model of food allergy.

Behav Brain Res 2014 Mar 12;261:265-74. Epub 2013 Dec 12.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.

Food allergy has been suggested to contribute to the expression of psychological and psychiatric traits, including disturbed social behaviour and repetitive behaviour inherent in autism spectrum disorders (ASD). Most research in this field receives little attention, since fundamental evidence showing direct effects of food allergic immune responses on social behaviour is very limited. In the present study, we show that a food allergic reaction to cow's milk protein, induced shortly after weaning, reduced social behaviour and increased repetitive behaviour in mice. This food allergic reaction increased levels of serotonin (5-hydroxytryptamine; 5-HT) and the number of 5-HT positive cells, and decreased levels of 5-hydroxyindoleacetic acid (5-HIAA) in the intestine. Behavioural changes in food allergic mice were accompanied by reduced dopaminergic activity in the prefrontal cortex. Furthermore, neuronal activation (c-Fos expression) was increased in the prefrontal cortex and reduced in the paraventricular nucleus of the hypothalamus after exposure to a social target. We hypothesize that an intestinal allergic response regulates complex, but critical, neuroimmune interactions, thereby affecting brain circuits involved in social interaction, repetitive behaviour and cognition. Together with a genetic predisposition and multiple environmental factors, these effects of allergic immune activation may exacerbate behavioural abnormalities in patients with ASD.
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http://dx.doi.org/10.1016/j.bbr.2013.12.008DOI Listing
March 2014

Longitudinal changes in the physical activity of adolescents with anorexia nervosa and their influence on body composition and leptin serum levels after recovery.

PLoS One 2013 21;8(10):e78251. Epub 2013 Oct 21.

Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands.

Objective: Patients with anorexia nervosa (AN) are often observed to have high levels of physical activity, which do not necessarily diminish after a successful therapy. Previous studies have shown that body fat tissue recovery in these patients is associated with a disproportional restoration of the adipocyte hormone, leptin. Therefore, we wondered whether the individual variation in physical activity in AN patients prior to treatment may be related to body fat percentage and plasma leptin level outcome.

Method: Body fat percentage, leptin serum, and physical activity levels (accelerometer) were measured in adolescents with an (n=37, age 13 to 17.5 years) at initial assessment, at the end of study participation (median 12 months), and at one-year follow-up.

Results: Accelerometer data were used to split the patients in two groups: those with low (n=26) and those with high levels of physical activity (HLPA, n=11). These groups did not differ in terms of age, IQ, presence of menses, BMI and season of admission. The HLPA group was characterized by a longer total duration of illness. Physical activity levels during therapy decreased for the group with initially HLPA and increased for the group with low levels of physical activity (to comparable levels). Physical activity remained stable after one year. The increase in body fat percentage and leptin levels were dependent on the recovery status; however, recovered patients with initially HLPA had significantly higher fat mass during the follow-up.

Discussion: HLPA, an important modulator of AN progression in adolescents, can be successfully diminished by therapeutic intervention. Among recovered patients, those with initially HLPA had higher fat mass levels than those with low levels of physical activity. This finding suggests that HLPA are an important modulator of the body composition recovery mechanism.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078251PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804495PMC
February 2015

Contactins in the neurobiology of autism.

Eur J Pharmacol 2013 Nov 17;719(1-3):63-74. Epub 2013 Jul 17.

Department of Neuroscience and Pharmacology, Brain Center Rudolf Magnus, UMC Medical Center Utrecht, 3584 CG Utrecht, The Netherlands. Electronic address:

Autism is a disease of brain plasticity. Inspiring work of Willem Hendrik Gispen on neuronal plasticity has stimulated us to investigate gene defects in autism and the consequences for brain development. The central process in the pathogenesis of autism is local dendritic mRNA translation which is dependent on axodendritic communication. Hence, most autism-related gene products (i) are part of the protein synthesis machinery itself, (ii) are components of the mTOR signal transduction pathway, or (iii) shape synaptic activity and plasticity. Accordingly, prototype drugs have been recognized that interfere with these pathways. The contactin (CNTN) family of Ig cell adhesion molecules (IgCAMs) harbours at least three members that have genetically been implicated in autism: CNTN4, CNTN5, and CNTN6. In this chapter we review the genetic and neurobiological data underpinning their role in normal and abnormal development of brain systems, and the consequences for behavior. Although data on each of these CNTNs are far from complete, we tentatively conclude that these three contactins play roles in brain development in a critical phase of establishing brain systems and their plasticity. They modulate neuronal activities, such as neurite outgrowth, synaptogenesis, survival, guidance of projections and terminal branching of axons in forming neural circuits. Current research on these CNTNs concentrate on the neurobiological mechanism of their developmental functions. A future task will be to establish if proposed pharmacological strategies to counteract ASD-related symptomes can also be applied to reversal of phenotypes caused by genetic defects in these CNTN genes.
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http://dx.doi.org/10.1016/j.ejphar.2013.07.016DOI Listing
November 2013

Fibroblast growth factors in neurodevelopment and psychopathology.

Neuroscientist 2013 Oct 23;19(5):479-94. Epub 2013 Jan 23.

Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, Netherlands.

In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology-directed treatments for psychopathology.
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http://dx.doi.org/10.1177/1073858412472399DOI Listing
October 2013

Intranasal mesenchymal stem cell treatment for neonatal brain damage: long-term cognitive and sensorimotor improvement.

PLoS One 2013 3;8(1):e51253. Epub 2013 Jan 3.

Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Centre Utrecht, Utrecht, The Netherlands.

Mesenchymal stem cell (MSC) administration via the intranasal route could become an effective therapy to treat neonatal hypoxic-ischemic (HI) brain damage. We analyzed long-term effects of intranasal MSC treatment on lesion size, sensorimotor and cognitive behavior, and determined the therapeutic window and dose response relationships. Furthermore, the appearance of MSCs at the lesion site in relation to the therapeutic window was examined. Nine-day-old mice were subjected to unilateral carotid artery occlusion and hypoxia. MSCs were administered intranasally at 3, 10 or 17 days after hypoxia-ischemia (HI). Motor, cognitive and histological outcome was investigated. PKH-26 labeled cells were used to localize MSCs in the brain. We identified 0.5 × 10(6) MSCs as the minimal effective dose with a therapeutic window of at least 10 days but less than 17 days post-HI. A single dose was sufficient for a marked beneficial effect. MSCs reach the lesion site within 24 h when given 3 or 10 days after injury. However, no MSCs were detected in the lesion when administered 17 days following HI. We also show for the first time that intranasal MSC treatment after HI improves cognitive function. Improvement of sensorimotor function and histological outcome was maintained until at least 9 weeks post-HI. The capacity of MSCs to reach the lesion site within 24 h after intranasal administration at 10 days but not at 17 days post-HI indicates a therapeutic window of at least 10 days. Our data strongly indicate that intranasal MSC treatment may become a promising non-invasive therapeutic tool to effectively reduce neonatal encephalopathy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0051253PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536775PMC
August 2013

Hyperactivity in anorexia nervosa: warming up not just burning-off calories.

PLoS One 2012 27;7(7):e41851. Epub 2012 Jul 27.

Department of Neuroscience & Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

Excessive physical activity is a common feature in Anorexia Nervosa (AN) that interferes with the recovery process. Animal models have demonstrated that ambient temperature modulates physical activity in semi-starved animals. The aim of the present study was to assess the effect of ambient temperature on physical activity in AN patients in the acute phase of the illness. Thirty-seven patients with AN wore an accelerometer to measure physical activity within the first week of contacting a specialized eating disorder center. Standardized measures of anxiety, depression and eating disorder psychopathology were assessed. Corresponding daily values for ambient temperature were obtained from local meteorological stations. Ambient temperature was negatively correlated with physical activity (p = -.405) and was the only variable that accounted for a significant portion of the variance in physical activity (p = .034). Consistent with recent research with an analogous animal model of the disorder, our findings suggest that ambient temperature is a critical factor contributing to the expression of excessive physical activity levels in AN. Keeping patients warm may prove to be a beneficial treatment option for this symptom.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041851PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407098PMC
April 2013

Mapping an X-linked locus that influences heat-induced febrile seizures in mice.

Epilepsia 2012 Aug 10;53(8):1399-410. Epub 2012 Jul 10.

Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.

Purpose: Febrile seizures (FS) are the most common seizure type in children between the age of 6 months and 5 years. Although FS are largely benign, recurrent FS are a major risk factor for developing temporal lobe epilepsy (TLE) later in life. The mechanisms underlying FS are largely unknown; however, family and twin studies indicate that FS susceptibility is under complex genetic control. We have recently developed a phenotypic screen to study the genetics of FS susceptibility in mice. Using this screen in a phenotype-driven genetic strategy we analyzed the C57BL/6J-Chr #(A)/NaJ chromosome substitution strain (CSS) panel. In each CSS line one chromosome of the A/J strain is substituted in a genetically homogeneous C57BL/6J background. The analysis of the CSS panel revealed that A/J chromosomes 1, 2, 6, 10, 13, and X carry at least one quantitative trait locus (QTL) for heat-induced FS susceptibility. The fact that many X-linked genes are highly expressed in the brain and have been implicated in human developmental disorders often presenting with seizures (like fragile X mental retardation) prompted us to map the chromosome X QTL.

Methods: C57BL/6J mice were mated with C57BL/6J-Chr X(A) /NaJ (CSSX) to generate F(2)-generations-CXBL6 and BL6CX-originating from CSSX or C57BL/6J mothers, respectively. Heat-induced FS were elicited on postnatal day 14 by exposure to a controlled warm airstream of 50°C. The latency to heat-induced FS is our phenotype. This phenotype has previously been validated by video-electroencephalography (EEG) monitoring. After phenotyping and genotyping the F(2)-population, QTL analysis was performed using R/QTL software.

Key Findings: QTL analysis revealed a significant peak with an LOD-score of 3.25. The 1-LOD confidence interval (149,886,866-158,836,462 bp) comprises 52 protein coding genes, of which 34 are known to be brain expressed. Two of these brain-expressed genes have previously been linked to X-linked epilepsies, namely Cdkl5 and Pdha1.

Significance: Our results show that the mouse genetics of X-linked FS susceptibility is complex, and that our heat-induced FS-driven genetic approach is a powerful tool for use in unraveling the complexities of this trait in mice. Fine-mapping and functional studies will be required to further identify the X-linked FS susceptibility genes.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03575.xDOI Listing
August 2012

Wireless implantable micro-stimulation device for high frequency bilateral deep brain stimulation in freely moving mice.

J Neurosci Methods 2012 Jul 5;209(1):113-9. Epub 2012 Jun 5.

Department of Psychiatry, UMC Utrecht, Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands.

Although deep brain stimulation (DBS) has been proven to be an effective treatment for several neuropsychiatric disorders, such as Parkinson's disease, the underlying working mechanisms are still largely unknown. Behavioral animal models are essential in examining the working mechanisms of DBS and especially mouse models are necessary to investigate the genetic component underlying specific behaviors related to psychiatric diseases. Unfortunately, currently available stimulation devices are unsuitable to test behavior in freely-moving mice. As such, no DBS studies in behaving mice have been reported thus far. In order to overcome this limitation we have developed a new light-weight wireless implantable micro stimulator device for mice that delivers biphasic pulse patterns to two individual electrode pairs, mimicking partly the clinical situation. This paper describes in detail the bench-top validation and in vivo implementation of this device. The results in this study indicate that the wireless implantable stimulator in mice reliably delivers continuous bilateral stimulation, importantly, does not restrict the animals mobility and hygiene (grooming behavior). In vivo testing furthermore showed that stimulation of the mice ventral striatum yields similar results as previously shown by others in rats where conventional deep brain stimulation techniques were used. This newly designed device can now be used in the highly needed DBS behavioral studies in mice, to further investigate the underlying mechanisms of DBS in behavioral animal models for psychiatric disorders.
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http://dx.doi.org/10.1016/j.jneumeth.2012.05.028DOI Listing
July 2012

Anorexia nervosa and the Val158Met polymorphism of the COMT gene: meta-analysis and new data.

Psychiatr Genet 2012 Jun;22(3):130-6

Department of Neuroscience, Rudolf Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands.

Objectives: This study aimed to test the association between the Val158Met polymorphism (rs4680) of the catechol-O-methyl transferase gene and anorexia nervosa (AN).

Methods: First, an association study on two cohorts (306 cases and 1009 controls from Utrecht, and 174 cases and 466 controls from Leiden/NTR) was performed. Subsequently, the results were integrated into a meta-analysis, together with all the case-control and family-based studies, which were testing the same hypothesis and were available in the literature. Altogether, eight studies (11 datasets) were included in this meta-analysis, with a total of 2021 cases, 2848 controls, and 89 informative (heterozygous) trios.

Results: The present association studies found no association between AN and rs4680 when testing the allelic contrast [Utrecht odds ratio (OR)=1.14, P=0.14; Leiden OR=1.02, P=0.85]. There was an indication of an association under the dominant model of genetic effect in the Utrecht cohort (for the Met allele, OR=1.42, P=0.03). Nevertheless, the meta-analyses of both the allelic contrast and the dominant effect were nonsignificant (the allelic pooled OR=1.03, P=0.42 and the dominant pooled OR=1.1, P=0.18). The meta-analyses were performed under the fixed-effect model and there was no significant heterogeneity among the effect sizes.

Conclusion: Meta-analytically combined evidence from the present genotypings and the literature search shows that the effect sizes are homogeneous across studies and that rs4680 is not associated with AN.
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http://dx.doi.org/10.1097/YPG.0b013e328351859eDOI Listing
June 2012

Sex-dependent novelty response in neurexin-1α mutant mice.

PLoS One 2012 13;7(2):e31503. Epub 2012 Feb 13.

Department of Neurosciences & Pharmacology, Division of Neuroscience, Rudolf Magnus Institute, University Medical Center Utrecht, The Netherlands.

Neurexin-1 alpha (NRXN1α) belongs to the family of cell adhesion molecules (CAMs), which are involved in the formation of neuronal networks and synapses. NRXN1α gene mutations have been identified in neuropsychiatric diseases including Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD). In order to get a better understanding of the pleiotropic behavioral manifestations caused by NRXN1α gene mutations, we performed a behavioral study of Nrxn1α heterozygous knock-out (+/-) mice and observed increased responsiveness to novelty and accelerated habituation to novel environments compared to wild type (+/+) litter-mates. However, this effect was mainly observed in male mice, strongly suggesting that gender-specific mechanisms play an important role in Nrxn1α-induced phenotypes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031503PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278455PMC
July 2012

Marked inbred mouse strain difference in the expression of quinpirole induced compulsive like behavior based on behavioral pattern analysis.

Eur Neuropsychopharmacol 2012 Sep 11;22(9):657-63. Epub 2012 Feb 11.

Department of Neuroscience and Pharmacology, UMC Utrecht, Rudolf Magnus Institute of Neuroscience, The Netherlands.

Obsessive-compulsive disorder (OCD) is a chronic and complex psychiatric disorder with a lifetime prevalence of 2-3%. Recent work has shown that OCD rituals were not only characterized by a high rate of repetition but also by an increased behavioral repertoire due to additional non-functional unique acts. These two behavioral characteristics may provide an ethological basis for studying compulsive behavior in an animal model of OCD. Here, quinpirole induced behavior (so far only investigated in rats) has been studied in A/J and C57BL/6J mice by using behavioral pattern analysis. The aim of this study is to investigate whether genetic background is mediating this behavior. Results showed that open field motor activity levels of saline treated C57BL/6J mice was significantly higher compared to A/J treated saline mice. Long-term quinpirole treatment increased open field motor activity levels in A/J, but not in C57BL/6J. Quinpirole treatment induced a strain dependent difference in behavioral repertoire. There was a dose dependent increase in the number of different behavioral patterns in A/J, whereas, in C57BL/6J there was a dose dependent decrease. This data suggest that genetic background is important in expressing quinpirole induced compulsive like behavior. Following quinpirole treatment, A/J mice express a greater behavioral repertoire with a high rate of repetition. This phenotype resembles that of OCD rituals in patients and indicates that this strain is very interesting to further validate for studying neurobiological mechanisms of compulsive behavior.
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http://dx.doi.org/10.1016/j.euroneuro.2012.01.003DOI Listing
September 2012

Current status and future prospects for epigenetic psychopharmacology.

Epigenetics 2012 Jan 1;7(1):20-8. Epub 2012 Jan 1.

Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, Utrecht, The Netherlands.

Mounting evidence suggest that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. These epigenetic regulatory mechanisms, such as DNA methylation and histone acetylation, are influenced by many pharmaceutical compounds including psychiatric drugs. It is therefore of interest to investigate how psychiatric drugs are of influence and what the potential is of new epigenetic drugs for psychiatric disorders. With this targeted review we summarize the current state of knowledge in order to provide insight in this developing field. Several traditional psychiatric drugs have been found to alter the epigenome and in a variety of animal studies, experimental compounds with epigenetic targets have been investigated as potential psychiatric drugs. After discussion of the most relevant epigenetic mechanisms we present the evidence for epigenetic effects for the most relevant classes of drugs.
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http://dx.doi.org/10.4161/epi.7.1.18688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329498PMC
January 2012

The Val66Met polymorphism of the BDNF gene in anorexia nervosa: new data and a meta-analysis.

World J Biol Psychiatry 2013 Aug 21;14(6):441-51. Epub 2011 Sep 21.

Department of Neuroscience & Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.

Objectives: The Val66Met polymorphism (rs6265) of the BDNF gene is a non-synonymous polymorphism, previously associated with anorexia nervosa (AN).

Methods: We genotyped rs6265 in 235 patients with AN and 643 controls. Furthermore, we performed a systematic review of all case-control and family-based studies testing this SNP in AN, and combined the results in a meta-analysis.

Results: The results of the case-control study were non-significant. For the meta-analysis, nine studies were identified (ncases = 2,767; ncontrols = 3,322, ntrios = 53) and included. Primarily, the analyses indicated an association with OR of 1.11 (P = 0.024) in the allelic contrast, and OR of 1.14 (P = 0.025) for the dominant effect of the Met allele. However, additional analyses revealed that the first published study (from those included in the meta-analysis) overly influenced the pooled effect size (possibly due to a phenomenon known as a winner's curse). When this case-control study was replaced by a trio study (ntrios = 293) performed on a largely overlapping sample, the effect size became smaller and non-significant, both for the allelic contrast (OR = 1.07, P = 0.156) and the dominant effect (OR = 1.07, P = 0.319). The quality of included studies was good and there was no significant heterogeneity across the effect sizes.

Conclusions: Our analyses indicate that the BDNF Val66Met variant is not associated with AN at detectable levels.
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http://dx.doi.org/10.3109/15622975.2011.605470DOI Listing
August 2013