Abstract
Rationale
The genetic heterogeneity of autism spectrum disorders (ASDs) is enormous, and the neurobiology of proteins encoded by genes associated with ASD is very diverse. Revealing the mechanisms on which different neurobiological pathways in ASD pathogenesis converge may lead to the identification of drug targets.
Objective
The main objective is firstly to outline the main molecular networks and neuronal mechanisms in which ASD gene products participate and secondly to answer the question how these converge. Finally, we aim to pinpoint drug targets within these mechanisms.
Method
Literature review of the neurobiological properties of ASD gene products with a special focus on the developmental consequences of genetic defects and the possibility to reverse these by genetic or pharmacological interventions.
Results
The regulation of activity-dependent protein synthesis appears central in the pathogenesis of ASD. Through sequential consequences for axodendritic function, neuronal disabilities arise expressed as behavioral abnormalities and autistic symptoms in ASD patients. Several known ASD gene products have their effect on this central process by affecting protein synthesis intrinsically, e.g., through enhancing the mammalian target of rapamycin (mTOR) signal transduction pathway or through impairing synaptic function in general. These are interrelated processes and can be targeted by compounds from various directions: inhibition of protein synthesis through Lovastatin, mTOR inhibition using rapamycin, or mGluR-related modulation of synaptic activity.
Conclusions
ASD gene products may all feed into a central process of translational control that is important for adequate glutamatergic regulation of dendritic properties. This process can be modulated by available compounds but may also be targeted by yet unexplored routes.
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Acknowledgments
Authors of this review were supported by EU-AIMS (European Autism Interventions), which receives support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115300, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (grant P7/2007–2013), from the European Federation of Pharmaceutical Industries and Associations companies’ in-kind contributions, and from Autism Speaks, resulting in a total of €29.6 million. N.B. was supported by the European Commission EUROSPIN and SynSys Consortia (FP7HEALTHF22009241498, FP7HEALTH F22009242167). D.D.K. is a recipient of a fellowship of the Alexander von Humboldt Foundation and a Marie Curie International Reintegration Grant of the European Commission. Research is further supported by the Deutsche Forschungsgemeinschaft (DFG, BO1718/4-1 to T.M.B.) and by the Baustein program of Ulm University (L.SBN.0081 to M.J.S.).
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Kleijer, K.T.E., Schmeisser, M.J., Krueger, D.D. et al. Neurobiology of autism gene products: towards pathogenesis and drug targets. Psychopharmacology 231, 1037–1062 (2014). https://doi.org/10.1007/s00213-013-3403-3
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DOI: https://doi.org/10.1007/s00213-013-3403-3