The Division of Molecular Psychiatry with the Research Unit on Disorders of Neurodevelopment and Cognition in conjunction with the Laboratory of Translational Neuroscience as part of the Center of Mental Health at the UKWürzburg (UKW) is leading in its field with an outstanding track record in psychiatric neuroscience research at the boundary between molecular genetics, cellular neurobiology and behaviour. Interdisciplinary and translational research strategies are employed to elucidate the pathogenesis of neurodevelopmental and a wide spectrum of life-spanning psychiatric disorders, ranging from depression and anxiety, psychotic (schizophrenia spectrum) and neurodegenerative disorders, to attention-deficit/hyperactivity, autism spectrum and substance use disorders (Kiser et al. 2015). Finally, mechanisms of pharmacologic and psychotherapeutic treatments are studied. To elucidate mechanisms of pathologically altered synaptic plasticity (synaptopathy), intraneuronal signaling (neuronal dysregulation) and interneuronal communication (system dysfunction) as well as their impact on the pathophysiology of psychiatric disease, the work uncompromisingly integrates pertinent research strategies. The long-term aim is to identify convergent pathways which could selectively be targeted by novel treatments (precision medicine). It accommodates core competences with unique methodological portfolios complementary to participating national and international collaborators. Broad experience in the design, generation and phenotyping of genetically modified mice and zebrafish allows the identification of factors that act as determinants of vulnerability to a spectrum of disorders. Each approach to pathophysiological mechanisms is using cutting edge and innovative methodology: Animals models are phenotyped at a behavioural level using a validated set of paradigms and at molecular, cellular and systems levels using, morphological techniques optogenetic/ electrophysiologic recordings in brain slices as well as transcriptomic/ epigenetic profiling and morpho-functional ultrahigh-field MRI.
Moreover, there is an increasingly successful track record in the search for functionally relevant common and rare variation in risk genes for psychiatric disorders by conducting genome-wide association studies and whole-exome/ genome sequencing in large cohorts and multiplex families segregating various unique neurodevelopmental disorders and psychiatric syndromes. Finally, the areas of convergence between the fields of neuropsychology, psycho- and neurobiology as well as child, adolescent and adult psychiatry are strengthening the connections between the individual disciplines by establishing and maintaining research groups, who are investigating mutual topics. In that, a unique environment for the study of the molecular and neural foundations in the etiopathogenesis and long-term course of neuropsychiatric disease has been put into practice. The overarching aim is to find pathways to “precision medicine” for psychiatry through understanding molecular and neuronal pathomechanisms of common disorders. The starting point for this is defined by the pertinent concept of neurodevelopmental and psychiatric disorders as synaptopathies. The strategy is that preclinical and clinically oriented research groups jointly work on molecular genetic and neurobiological essentials of brain function and specific molecular mechanisms of neuronal cell activity as well as on the structural-functional basis of psychiatric disorder-related complex behaviour. Predictors/ biomarkers and differential strategies for innovative therapy during the long-term course of illness are also developed. Specifically, the goal comprises 1) a translational axis for endophenotypic profiling of neurodevelopmental/ psychiatric disease in behavioural, (epi)genetic and neurophysiologic terms, and 2) a platform for the elucidation of pathogenetic brain mechanisms and thereby the development of personalised therapies for neurodevelopmental/ psychiatric disease and their comorbidities. In order to achieve this goal the following primary objectives are pursued:
- Identification of common and rare variation in risk genes using genome-wide approaches (GWAS, CNV screening, whole-exome/genome sequencing) (e.g. O’Dushlaine et al. 2015). A database for selected multiplex families with high density of ADHD, psychotic and bipolar disorder (30-40 members per family) has been set up. 24 of these extended pedigrees have already been collected and subjected to genome-wide screening approaches, including whole-exome/genome sequencing and the assembly of another 20-25 families is planned.
- Validation of genetic findings and integrative genomic approaches through advances in the development of model systems of increasing complexity by combining (epi-)genetics approaches with bioinformatics, mutation-specific iPSC lines and animal models (targeted gene modification in mouse and zebrafish) to understand disease mechanisms (e.g. Gutknecht et al. 2015).
- Integration of gene expression-neuroimaging-cognition data sets of well characterised cohorts and extended pedigrees to bridge the gap between genome-wide screenings and testable pathophysiological hypotheses and to push forward the understanding of the neurobiology leading from gene to cognitive dysfunction and disease.
- Investigation of epigenetic programming by early-life stressors in genetically modified mouse models subjected to maternal deprivation und andere Stressoren (GxE mouse models) that simulate neurobehavioural characteristics of psychiatric disorders (e.g. 5-Htt, Tph2, Cdh13 and Lphn3 knockout mouse models) (e.g. Schraut et al. 2014).
- Translation of novel epigenetically regulated psychiatric disease-related risk genes derived from GxE mouse models in human cohorts characterised for environmental adversity that exhibit disease-associated traits/behaviour and determine their utility as biomarkers.
- Investigation of the excitatory-inhibitory dysbalance reflecting the pertinent concept of synaptopathy in neurodevelomental and psychiatric disorders: Our contribution to the discovery of variation affecting genes encoding glutamate receptors (e.g. metabotropic glutamate receptor-5, GRM5) and mediators of their intracellular signalling pathways (e.g. nitric oxide synthase-1, NOS1) as well as molecules interacting in the formation and plasticity of glutamatergic (e.g. latrophilin-3, LPHN3) and GABAergic (e.g. CDH13) synapses as relevant causative factors point to compromised monoamine-glutamate-GABA system interaction in neurodevelopmental/psychiatric disorders. Synaptic adhesion molecules, receptors and mediators of intracellular signalling pathways are principal components of the molecular machinery that connect pre- and postsynaptic neurons, facilitate transmission, control synaptic plasticity and empower intersecting neural circuits to process and refine information. These mechanisms require meticulous dissection at several levels of complexity to pinpoint dysfunction related to disease mechanisms, using cellular, in vivo animal models and neural systems using neuroimaging (e.g. Rivero et al. 2015).
- Exploration alternative disease definitions based on the discovery of molecular, cellular and systems-related disease mechanisms for various neurodevelopmental/psychiatric disorders, which are currently primarily defined by symptoms, rather than by aetiology. Finally, work towards precision treatment has been initiated: use novel cognitive assessments to evaluate non-pharmacological treatment options, in addition to developing new compounds for pharmacological treatment optimisation and individualisation. The basis for the pursuit of these objectives is the interdisciplinary composition of the group and its integration into a wide spectrum of local, national (e.g. Transregio 58, ERA-NET/BMBF consortia) and international collaborations (e.g. IMpACT, MiND, NIMH, NICHD, NHGRI, NIDA, NIAAA, Stony Brook, EMBL, Karolinska Institute, Universities of Maastricht, Nijmegen, Paris, Oxford, Shanghai, Bergen, Rome, Florence, Barcelona, Lisbon, Budapest and Tartu, to name only a few). For example, IMpACT (http://impactadhdgenomics.com), is a consortium of clinical and basic researchers from several European countries (The Netherlands, Spain, Norway, UK, Sweden, Denmark) as well as from the USA and Brazil focussing on all aspects of ADHD across the lifespan. This consortium boasts to have collected a cohort of 18,000+ patients with ADHD.