J Psychiatry Neurosci 2017;42(1):48-58
Michael Didriksen, PhD; Kim Fejgin, PhD; Simon R.O. Nilsson, PhD; Michelle R. Birknow, MSc; Hannah M. Grayton, PhD; Peter H. Larsen, PhD; Jes B. Lauridsen, PhD; Vibeke Nielsen, BSc; Pau Celada, PhD; Noemi Santana, PhD; Pekka Kallunki, PhD; Kenneth V. Christensen, PhD; Thomas M. Werge, PhD; Tine B. Stensbøl, PhD; Jan Egebjerg, PhD; Francois Gastambide, PhD; Francesc Artigas, PhD; Jesper F. Bastlund, PhD; Jacob Nielsen, PhD
Background: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neurodevelopmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms.
Methods: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice.
Results: We found elevated postpubertal N-methyl-D-aspartate (NMDA) receptor antagonist–induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays.
Limitations: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors that may unmask latent psychopathology.
Conclusion: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the etiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.
Submitted Jan. 6, 2016; Revised Mar. 5, 2016; Accepted Apr. 5, 2016; Early-released July 12, 2016
Acknowledgements: The research leading to these results was conducted as part of NEWMEDS and received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement 115008, of which resources are composed of an EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). This work was further supported by grants from the Danish Advanced Technology Foundation (File no. 001-2009-2) and by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). We thank the technical staff for skillful assistance.
Affiliations: From H. Lundbeck A/S, Research DK, Valby, Denmark (Didriksen Fejgin, Birknow, Larsen, Lauridsen, Nielsen, Kallunki, Christensen, Stensbøl, Egebjerg, Nielsen); the Department of Psychology, University of Cambridge, Cambridge, UK (Nilsson); the Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK (Nilsson); the Lilly Centre for Cognitive Neuroscience, Lilly Research Laboratories, Windlesham, UK (Grayton, Gastambide); the Institut d’Investigacions Biomèdiques de Barcelona, Barcelona, Spain (Celada, Artigas); the Centro de Investigación Biomédica en Red de Salud Mental, Spain (Santana, Artigas); the Institute of Biological Psychiatry, MHC Sct. Hans, Copenhagen Mental Health Services; and the Institute of Clinical Sciences, Faculty of Medicine and Health Sciences, University of Copenhagen; iPSYCH – The Lundbeck Foundation’s Initiative for Integrative Psychiatric Research, Roskilde, Denmark (Werge).
Competing interests: M. Didriksen, V. Nielsen, P. Kallunki, K. Christensen, T. Stensbøl, J. Egebjerg and J. Bastlund are employees and shareholders of H. Lundbeck A/S. K. Fejgin, M. Birknow, P. Larsen, J. Lauridsen and J. Nielsen are employees of H. Lundbeck A/S. M. Birknow has received personal fees from Innovation Fund Denmark. H. Grayton and F. Gastambide are employees of Eli Lilly & Co. Ltd, UK. T. Werge has received consultant and lecture fees from H. Lundbeck A/S. F. Artigas has received consultant fees from Lundbeck A/S and is member of the scientific advisory board of Neurolixis. He is also coinventor of patents on RNAi technologies in collaboration with nLife Therapeutics. No other competing interests declared.
Contributors: M. Didriksen, K. Fejgin, M. Birknow, J. Lauridsen, V. Nielsen, P. Kallunki, K/ Christensen, T. Werge, T. Stensbøl, J. Egebjerg, F. Gastambide, F. Artigas, J. Bastlund and J. Nielsen designed the study. M. Didriksen, K. Fejgin, M. Birknow, H. Grayton, P. Larsen, J. Lauridsen, V. Nielsen, P. Celada, N. Santana, P. Kallunki, K. Christensen, F. Gastambide and J. Bastlund acquired and analyzed the data, which S. Nilsson, F. Artigas and J. Nielsen also analyzed. M. Didriksen, S. Nilsson, M. Birknow, H. Grayton, P. Larsen, J. Lauridsen, V. Nielsen, P. Celada, N. Santana, P. Kallunki, T. Werge, F. Gastambide, F. Artigas, J. Bastlund and J. Nielsen wrote the article, which all authors reviewed and approved for publication.
Correspondence to: M. Didriksen, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; email@example.com