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Psychopharmacology

, Volume 231, Issue 6, pp 1037–1062 | Cite as

Neurobiology of autism gene products: towards pathogenesis and drug targets

  • Kristel T. E. Kleijer
  • Michael J. Schmeisser
  • Dilja D. Krueger
  • Tobias M. Boeckers
  • Peter Scheiffele
  • Thomas Bourgeron
  • Nils Brose
  • J. Peter H. Burbach
Review

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.

Keywords

Autism spectrum disorders Autism genetics Dendritic protein synthesis Autism drug targets Neurexin Neuroligin SHANK CNTNAP2 PTEN Fragile X syndrome mouse models 

Notes

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.).

Conflict of interest

No conflicts of interest are reported.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Kristel T. E. Kleijer
    • 1
  • Michael J. Schmeisser
    • 2
  • Dilja D. Krueger
    • 3
  • Tobias M. Boeckers
    • 2
  • Peter Scheiffele
    • 4
  • Thomas Bourgeron
    • 5
  • Nils Brose
    • 3
  • J. Peter H. Burbach
    • 1
  1. 1.Department Translational Neuroscience, Brain Center Rudolf MagnusUniversity Medical Center UtrechtUtrechtThe Netherlands
  2. 2.Institute for Anatomy and Cell BiologyUlm UniversityUlmGermany
  3. 3.Department of Molecular NeurobiologyMax Planck Institute of Experimental MedicineGoettingenGermany
  4. 4.Biozentrum, University of BaselBaselSwitzerland
  5. 5.Human Genetics and Cognitive FunctionsInstitute PasteurParis Cedex 15France

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