Elsevier

Biological Psychiatry

Volume 76, Issue 2, 15 July 2014, Pages 128-137
Biological Psychiatry

Archival Report
A Mouse Model that Recapitulates Cardinal Features of the 15q13.3 Microdeletion Syndrome Including Schizophrenia- and Epilepsy-Related Alterations

https://doi.org/10.1016/j.biopsych.2013.08.014Get rights and content

Background

Genome-wide scans have uncovered rare copy number variants conferring high risk of psychiatric disorders. The 15q13.3 microdeletion is associated with a considerably increased risk of idiopathic generalized epilepsy, intellectual disability, and schizophrenia.

Methods

A 15q13.3 microdeletion mouse model (Df[h15q13]/+) was generated by hemizygous deletion of the orthologous region and characterized with focus on schizophrenia- and epilepsy-relevant parameters.

Results

Df(h15q13)/+ mice showed marked changes in neuronal excitability in acute seizure assays, with increased propensity to develop myoclonic and absence-like seizures but decreased propensity for clonic and tonic seizures. Furthermore, they had impaired long-term spatial reference memory and a decreased theta frequency in hippocampus and prefrontal cortex. Electroencephalogram characterization revealed auditory processing deficits similar to those observed in schizophrenia. Gamma band power was increased during active state, but evoked gamma power following auditory stimulus (40 Hz) was dramatically reduced, mirroring observations in patients with schizophrenia. In addition, Df(h15q13)/+ mice showed schizophrenia-like decreases in amplitudes of auditory evoked potentials. Although displaying a grossly normal behavior, Df(h15q13)/+ mice are more aggressive following exposure to mild stressors, similar to what is described in human deletion carriers. Furthermore, Df(h15q13)/+ mice have increased body weight, and a similar increase in body weight was subsequently found in a sample of human subjects with 15q13.3 deletion.

Conclusions

The Df(h15q13)/+ mouse shows similarities to several alterations related to the 15q13.3 microdeletion syndrome, epilepsy, and schizophrenia, offering a novel tool for addressing the underlying biology of these diseases.

Section snippets

Human Subjects

Four male and 11 female subjects (mean age 54 ± 16.0 years) were identified using deCODE’s database of 95,085 genotyped Icelandic individuals after excluding psychiatric phenotypes (autism, schizophrenia, and bipolar disorder) and individuals receiving antipsychotic drugs. Control subjects (40 male subjects, 110 female subjects) were matched for year of birth and sex from the database. All subjects provided written, informed consent for participation, and approval was obtained from the National

Basic Behavior and Physiology Is Normal in Df(h15q13)/+ Mice

A mouse model of the human 15q13.3 deletion syndrome was generated by deletion of the orthologous genomic region on mouse chromosome 7. Animals were born at expected ratios (hemizygous fraction .52, 95% confidence interval: .39 to .64), but survival of Df(h15q13)/+ pups at weaning was slightly reduced with a hemizygous fraction of .45 (95% confidence interval: .42 to .47, n = 488/1084). For further characterization, hemizygous male mice were compared with wild-type littermates.

Overall,

Discussion

We have generated a mouse model of the human 15q13.3 microdeletion syndrome that recapitulates some physiological and behavioral characteristics of the human carriers. We have focused on schizophrenia and epilepsy aspects (Table S2 in Supplement 1) due to the strong association with these disorders, but we serendipitously discovered aggression and weight phenotypes that are also present in human microdeletion carriers. Several groups have reported aggressive behavior in carriers of the 15q13.3

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    Authors KF and JN contributed equally to this work.

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