KFO 125: Attention Deficit/Hyperactivity Syndrome (ADHD): Molecular Pathogenesis and Endophenotypes in the Course of Treatment
Final Report Abstract
The pathogenesis of Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly relevant but largely unsolved problem. The burden of disease and the unmet clinical needs cannot be overestimated by accounts of social and economic problems as well as impaired academic achievement and work performance. The Clinical Research Unit on ADHD (CRU 125), as a joint facility of the Department of Child and Adolescent Psychiatry and the Department of Psychiatry, has been investigating the relationships between the molecular and functional-structural mechanisms of the pathogenesis of ADHD and long-term course using inter- and multidisciplinary as well as translational research strategies. The primary aims had been based on the following concept: By joining preclinical and clinically oriented research groups, who work on ADHD-specific molecular mechanisms of neuronal cell activity as well as molecular genetic and developmental biological essentials of brain function, and on structural-functional basis of ADHD-related complex behavior, predictors and differential strategies for therapy during the long-term course of illness have been developed. Moreover, evolutionary conserved ADHD-relevant principles of structure and function of the brain as well as syndrome-typical behavior (e.g., hyperactivity, attention-deficit, impulsivity, aggression, substance use) have been defined by comparative investigations of different species (humans, nonhuman primates, mice, zebrafish). Finally, the preexisting areas of convergence between the fields of neuropsychology, psychobiology as well as psychiatry have been strengthening the links between the individual disciplines by establishing new research groups focussing on common topics. In that, new opportunities for the study of the molecular and cellular foundations in the etiopathogenesis and long-term course of ADHD have been put into practice. Several scientific milestones have been reached with the contribution of the CRU 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 interacting molecules in the formation and plasticity of glutamatergic (e.g. latrophilin-3, LPHN3) and GABAergic (e.g. CDH13) synapses as relevant causative factors. Research on ADHD pathogenesis is therefore increasingly shifting focus to dopamine-glutamate-GABA system interaction. Based on genome-wide screenings for ADHD-related risk genes revealed a remarkable and ever increasing number of common and rare variants encoding synaptic adhesion molecule, receptors for glutamate and mediators of intracellular signalling pathways. These principal components of the molecular machinery connect pre- and postsynaptic neurons, facilitate neurotransmission, control synaptic plasticity and empower intersecting neural circuits to process and refine information. Brain function is contingent on structured patterns of connections between neurons of distinct specification. The formation of this connectivity entails the targeting of axons to dendrites of demarcated circuits, the recognition of individual target neurons, the formation of synapses on precise regions of the dendritic tree, and the differentiation of pre- and postsynaptic specializations. These findings also suggest that the coordinated actions of a number of molecular signals contribute to the specification and differentiation of synaptic connections in the developing and adult brain, as elicited by electrophysiological and neuropsychological paradigms as well as brain imaging techniques including EEG, NIRS, fMRI. The basis for the pursuit of these concepts and goals was the interdisciplinary composition of CRU and its integration into the research structures of the University of Wuerzburg (e.g. SFB 581, SFB TRR 58, CHFC, IZKF,) as well as into a wide spectrum of national (e.g. BMBF Multicentre ADHD Treatment Study, Nationales Schwerpunktnetzwerk ADHS, MPI für Molekulare Genetik) and international collaborations (e.g. IMpACT, IMAGE2, NIMH, NHGRI, NIDA, NIAAA, Maastricht University, University of Tartu). This resulted in a long-term configuration of competence at the University of Wuerzburg and an enhancement of the interdisciplinarity of teaching in the psychiatric neurosciences (e.g. GRK 1253, GSLS, ITN) with focus on translational research of the etiopathogenetic mechanisms of ADHD.
