A Mouse Model that Recapitulates Cardinal Features of the 15q13.3 Microdeletion Syndrome

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Michelle Rosgaard Birknow, MSc in Biomedical Engineering, Industrial PhD Student, H. Lundbeck A/S

Recent research has led to the discovery of rare copy number variations (CNVs) that confer high risk of psychiatric disorders.  The 15q13.3 microdeletion is a recently discovered CNV that increases the risk of developing schizophrenia (OR~11) and epilepsy (OR~68).

Currently, there is a lack of animal models with face or construct validity for schizophrenia, which makes it difficult to explore the underlying pathogenesis and to develop new treatment. Copy number variations are promising starting points for developing animal models with construct validity. The human 15q13.3 locus is conserved within the syntenic region of the mouse chromosome 7, which harbors the orthologs of the human genes. This has made it possible to make a mouse model of the human microdeletion syndrome. The generation of a genetic mouse model of the deletion syndrome is a starting point towards achieving better understanding of the underlying disease mechanisms as well as development of translational assays that can be used to develop novel drugs for schizophrenia patients.

In this study, we have, for the first time, generated a 15q13.3 microdeletion mouse model (Df(h15q13)/+) and characterized it with focus on schizophrenia- and epilepsy-relevant parameters, due to the strong association with these disorders.

The study demonstrated that the Df(h15q13)/+ mice show similarities to alterations seen in the human 15q13.3 microdeletion syndrome, including increased aggression and body weight. In addition, a complex but pronounced seizure phenotype was identified in the Df(h15q13)/+ mice.  Df(h15q13)/+ mice showed increased propensity to develop absence-like seizures but were protected from developing full-blown clonic tonic seizures. Notably, although several psychiatric phenotypes are difficult to evaluate in animal models, Df(h15q13)/+ mice also exhibited a number of features relevant to schizophrenia, such as auditory processing deficits (measured by EEG) and impaired long-term spatial reference memory, which demonstrates the translational potential of this novel animal model.

In conclusion, the 15q13.3 microdeletion mouse model displays several features resembling the clinical syndrome, including changes in schizophrenia-relevant domains and seizure susceptibility. Thus, the 15q13.3 microdeletion mouse model constitutes a novel tool for addressing the underlying biology of these diseases.

The article ”A mouse model that recapitulates cardinal features of the 15q13.3 microdeletion syndrome including schizophrenia- and epilepsy-related alterations” was published in Biological Psychiatry,  2014 Jul 15; 76(2):128-37.

Facts about the study

  • The 15q13.3 microdeletion encompasses an approximately 1.5-megabase region harboring following six genes (MTMR15, MTMR10, TRPM 1, KLF13, OTUD7A and CHRNA7)
  • Transgenic mice carrying the ortholog deletion of 15q13.3 (mouse: 16qA3) have been generated by H. Lundbeck A/S.

Further information:

Michelle Rosgaard Birknow, MSc in Biomedical Engineering, Industrial PhD Student, H. Lundbeck A/S, Email: mrbi@lundbeck.com