Many psychiatric disorders in children and adolescents - autism, ADHD, mental retardation and schizophrenia - are associated with disorders of brain development. They do not arise suddenly but develop before birth, during childhood and adolescence. To improve our understanding of these neurobiological mechanisms, we use both molecular and behavioral techniques as well as epidemiological methods to explore global and social cognition. One research approach is to study the pharmacological class of mTOR inhibitors in the treatment of an autism-like phenotype in the Tsc2+/- (Eker) rats animal model. The goal is to transfer the neurobiological findings on possible experimental therapies in humans. Another approach is to study the validity of patient history data collected for development in infancy and childhood for diagnostic purposes in adolescence.
The Tsc2+/- (Eker) rat, a Tsc2+/- spontaneous mutation, has been known since the 1960s. We discovered that the Tsc2+/- (Eker) rat shows an autism-like phenotype that can be additionally reinforced by epilepsy (Waltereit et al. 2006, Waltereit et al. 2011). We are currently investigating the effect of the mTOR inhibitor everolimus on the autism-like phenotype of Tsc2+/- (Eker) rats. Hence, there are indications of a possible experimental therapy of autistic behavior.
Project A: "Effect of everolimus on TSC2 mutation versus epilepsy"
Tuberous sclerosis leads to autism, mental retardation and epilepsy, and can be studied in TSC2 animal models (Waltereit et al. 2006, von der Brelie et al. 2006, Waltereit et al. 2011). We are currently investigating the effect of the mTOR inhibitor everolimus on autism-like behavior in Tsc2+/- (Eker) rats. With this project we additionally want to investigate how everolimus acts on the TSC2 mutation and epilepsy induced deficits, respectively.
Project B: "Investigation of the regulation of neuroplasticity genes in the context of the mTOR complex"
Arg3.1 / arc is a key neuroplasticity gene (Plath et al. 2006). It is regulated by MAPK (Waltereit et al. 2001). Arg3.1 / arc is also a gene whose malfunction is increasingly associated with autism. The MAPK signaling pathway in the brains of Tsc2+/- (Eker) rats is increased (Waltereit et al. 2006). In this project we want to investigate the regulation of neuroplasticity genes such as Arg3.1 / arc and additionaly analyse the MAPK and mTOR signaling pathways in Tsc2+/- (Eker) rats.
Project C "Anamnestic markers of developmental disorders"
Patient history data for development are routinely collected in the clinic. However, there are still no systematic studies to what extent anamnestic developmental data are related to specific profiles that refer to specific subsequent diseases. In this study routinely collected anamnestic developmental data will be compared to a followup examination and then put into perspective for clinical diagnosis in adolescence.
Prof. Dr. Christine Winter, Experimentelle Psychiatrie, Clinic for Psychiatry and Psychotherapy, Universitäty Hospital Carl Gustav Carus
PD Dr. Miriam Schneider, Developmental Neuropsychopharmacology, Zentralinstitut für Seelische Gesundheit Mannheim, University Heidelberg
Prof. Dr. Petrus de Vries, Division of Child and Adolescent Psychiatry, University of Cape Town, South Africa
Deutsche Tuberöse Sklerose Stiftung, Novartis
Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis. Waltereit R, Welzl H, Dichgans J, Lipp HP, Schmidt WJ, Weller M. J Neurochem. 2006 Jan;96(2):407-13. Epub 2005 Nov 21.
Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories. Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C, Mao X, Engelsberg A, Mahlke C, Welzl H, Kobalz U, Stawrakakis A, Fernandez E, Waltereit R, Bick-Sander A, Therstappen E, Cooke SF, Blanquet V, Wurst W, Salmen B, Bösl MR, Lipp HP, Grant SG, Bliss TV, Wolfer DP, Kuhl D. Neuron. 2006 Nov 9;52(3):437-44.
Epilepsy and Tsc2 haploinsufficiency lead to autistic-like social deficit behaviors in rats. Waltereit R, Japs B, Schneider M, de Vries PJ, Bartsch D. Behav Genet. 2011 May;41(3):364-72. doi: 10.1007/s10519-010-9399-0. Epub 2010 Oct 7.
Srgap3⁻/⁻ mice present a neurodevelopmental disorder with schizophrenia-related intermediate phenotypes. Waltereit R, Leimer U, von Bohlen Und Halbach O, Panke J, Hölter SM, Garrett L, Wittig K, Schneider M, Schmitt C, Calzada-Wack J, Neff F, Becker L, Prehn C, Kutscherjawy S, Endris V, Bacon C, Fuchs H, Gailus-Durner V, Berger S, Schönig K, Adamski J, Klopstock T, Esposito I, Wurst W, de Angelis MH, Rappold G, Wieland T, Bartsch D. FASEB J. 2012 Nov;26(11):4418-28. doi: 10.1096/fj.11-202317. Epub 2012 Jul 20.
Interaction of neurodevelopmental pathways and synaptic plasticity in mental retardation, autism spectrum disorder and schizophrenia: implications for psychiatry. Waltereit R, Banaschewski T, Meyer-Lindenberg A, Poustka L. World J Biol Psychiatry. 2014 Sep;15(7):507-16. doi: 10.3109/15622975.2013.838641. Epub 2013 Sep 30.
Unsolicited applications for medical theses and psychological or biological master theses are welcome!