Fig. 1: Known structural effects of impaired SERT activity in the rodent brain. SERT dysfunction during early brain development results in distinct changes in corticolimbic (red) and somatosensory thalamocortical (blue) structures. In the corticolimbic system, SERT-KO leads (a) to increased dendritic spine densities in pyramidal cells of the amygdala and (b) abnormally increased dendritic branching in pyramidal neurons of the prefrontal cortex. In the somatosensory systems, SERT-KO as well as exposure to SSRIs (fluoxetine) during early development causes (c) impaired innervation of cortical layer IV by distinctively reduced arborisation of thalamocortical axon clusters, (d) diffuse barrel patterns and (e) dendritically smaller spiny stellate cells with a reduced spine density. Brain regions and related pathways, which are noted for rodents here, have analogues in human brains with comparable or identical nomenclature and function (from Homberg, Schubert & Gaspar, Trends Pharmacol Sci 2010;31:60-5).

RESPOND

(Research on Serotonin in the Pathogenesis Of Neurodevelopmental Disorders)

RESPOND responds to the increasing burden on patients and societies imposed by neurodevelopmental disorders such as attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and schizophrenia. The neurotransmitter serotonin has been implicated in the pathogenesis of these diseases and is a known regulator of neurodevelopment. However, the relevance of serotonin for the pathogenesis of these diseases and the involved mechanisms remain to be clarified. RESPOND will analyze neurodevelopmental processes and disease-related behavior in three novel rat strains with targeted genetic alterations in two major components of the serotonin system, TPH2, the serotonin-synthesizing enzyme, and SERT, the serotonin reuptake transporter. Rats offer more suitable behavioral assays for the research on ADHD, ASD, and schizophrenia than mice and are therefore the preferred animal model. In parallel pluripotent stem cells will be isolated from patients with these diseases and from the rats with dysregulated central serotonin system and used to assess alterations in differentiation and in-vitro as well as in-vivo development. The five partners from Germany, Poland, France, and The Netherlands will join their highly complementary expertise in RESPOND to provide a comprehensive description of serotonin’s role in neurodevelopmental disorders and eventually establish novel animal and cellular models for the development of therapies for ADHD, ASD, and schizophrenia.

Partners:

Germany	Michael Bader, Natalia Alenina	Max-Delbrück-Center for Molecular Medicine (MDC), Berlin
Germany	Klaus-Peter Lesch, Frank Edenhofer	Division of Molecular Psychiatry, University Hospital Würzburg, Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg
Poland	Piotr Popik, Agnieszka Nikiforuk	Institute of Pharmacology, Polish Academy of Sciences, Krakow
France	Patricia Gaspar, Stephane Nedelec	Inserm, UMR-S 839, Paris
The Netherlands	Judith Homberg	Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behavior, Department of Cognitive Neuroscience, Nijmegen