Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Nov;44(12):2125-2135.
doi: 10.1038/s41386-019-0441-5. Epub 2019 Jun 19.

Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome

Masayuki Baba  1 , Kazumasa Yokoyama  2 , Kaoru Seiriki  1   3 , Yuichiro Naka  1 , Kensuke Matsumura  1   3   4 , Momoka Kondo  1 , Kana Yamamoto  1 , Misuzu Hayashida  1 , Atsushi Kasai  1 , Yukio Ago  1   5 , Kazuki Nagayasu  1 , Atsuko Hayata-Takano  1   6 , Akinori Takahashi  7 , Shun Yamaguchi  8   9 , Daisuke Mori  10   11 , Norio Ozaki  10 , Tadashi Yamamoto  7   12 , Kazuhiro Takuma  6   13 , Ryota Hashimoto  14   15 , Hitoshi Hashimoto  16   17   18   19 , Takanobu Nakazawa  20   21
Affiliations

Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome

Masayuki Baba et al. Neuropsychopharmacology. 2019 Nov.

Abstract

3q29 microdeletion, a rare recurrent copy number variant (CNV), greatly confers an increased risk of psychiatric disorders, such as schizophrenia and autism spectrum disorder (ASD), as well as intellectual disability. However, disease-relevant cellular phenotypes of 3q29 deletion syndrome remain to be identified. To reveal the molecular and cellular etiology of 3q29 deletion syndrome, we generated a mouse model of human 3q29 deletion syndrome by chromosome engineering, which achieved construct validity. 3q29 deletion (Df/+) mice showed reduced body weight and brain volume and, more importantly, impaired social interaction and prepulse inhibition. Importantly, the schizophrenia-related impaired prepulse inhibition was reversed by administration of antipsychotics. These findings are reminiscent of the growth defects and neuropsychiatric behavioral phenotypes in patients with 3q29 deletion syndrome and exemplify that the mouse model achieves some part of face validity and predictive validity. Unbiased whole-brain imaging revealed that neuronal hyperactivation after a behavioral task was strikingly exaggerated in a restricted region of the cortex of Df/+ mice. We further elucidated the cellular phenotypes of neuronal hyperactivation and the reduction of parvalbumin expression in the cortex of Df/+ mice. Thus, the 3q29 mouse model provides invaluable insight into the disease-causative molecular and cellular pathology of psychiatric disorders.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Characterization of Df/+ mice, a mouse model for the human 3q29 deletion. a The deleted region in human chromosome 3q29 (top) and the syntenic region in mouse 16B2,3 (bottom). b Decreased body size in Df/+ mice (12 weeks old). Scale bar, 1 cm (left). Quantification of body weight in WT and Df/+ mice (WT, n = 23; Df/+, n = 22) (right). **P < 0.01, repeated two-way analysis of variance (ANOVA). WT, wild-type littermates. c Decreased body weight in Df/+ mice (embryonic day 18.5) (WT, n = 18; Df/+, n = 11). *P < 0.05, Student’s t test. d Reduced brain weight in Df/+ mice (12 weeks old) (WT, n = 10; Df/+, n = 10). ***P < 0.001, Student’s t test. e Messenger RNA (mRNA) expression changes in the cerebral cortex measured by RNA sequencing in 12-week-old Df/+ mice compared to WT mice (each n = 3). *Corrected P < 0.05, unpaired t test with Benjamin–Hochberg false discovery rate correction. Data are presented as the mean ± s.e.m.
Fig. 2
Fig. 2
Psychiatric disorder-related behavioral phenotypes in Df/+ mice. a Increased startle amplitude in Df/+ mice (WT, n = 10; Df/+, n = 10). *P < 0.05, one-way analysis of variance (ANOVA). WT, wild-type littermates. b Impaired prepulse inhibition (PPI) in Df/+ mice (WT, n = 10; Df/+, n = 10). *P < 0.05, repeated two-way ANOVA with Bonferroni post hoc tests. c Impaired social interaction in Df/+ mice (WT, n = 10; Df/+, n = 10). *P < 0.05, one-way ANOVA. d Increased self-grooming activity (an index of repetitive behavior) in Df/+ mice (WT, n = 10; Df/+, n = 10). *P < 0.05, one-way ANOVA. e Impaired fear conditioning in Df/+ mice (WT, n = 10; Df/+, n = 9). *P < 0.05, one-way ANOVA. f Increased open-field activity in Df/+ mice (WT, n = 8; Df/+, n = 9). *P < 0.05, one-way ANOVA. g Time in the center zone during the first 5 min in the open-field test (WT, n = 8; Df/+, n = 9). h Rescue of the increased startle amplitude by risperidone administration in Df/+ mice (each n = 10). *P < 0.05, **P < 0.01, two-way ANOVA with Bonferroni post hoc tests. i Rescue of the impaired PPI by risperidone administration in Df/+ mice (each n = 10). *P < 0.05, two-way ANOVA with Bonferroni post hoc tests. The percent of the PPI at all dB levels was not significantly different between risperidone-treated Df/+ and WT mice (68 dB, P = 0.557; 71 dB, P = 0.326; 74 dB, P = 0.318). Data are presented as the mean ± s.e.m.
Fig. 3
Fig. 3
Increased expression of immediate early genes in the cortex of Df/+ mice. a Top-ranked differentially expressed genes in the mouse cortex between wild-type (WT) and Df/+ mice (RNA sequence, |FC| > 2, P < 0.05) (WT, n = 3; Df/+, n = 3). Note that the deleted genes in the 16B2, 3 region were not listed in the table (see Fig. 1e). b The expression of each immediately early gene was assayed by reverse transcription PCR (RT-PCR) using total RNA from the cerebral cortex (WT, n = 4; Df/+, n = 5). *P < 0.05, **P < 0.01, Student’s t test. Data are presented as the mean ± s.e.m.
Fig. 4
Fig. 4
Unbiased whole-brain activation mapping after social interaction. a Representative whole-brain imaging of Df/+ mice and wild-type (WT) littermates carrying Arc-dVenus transgene subjected to the social interaction. Whole-brain images. Scale bar, 2 mm (left). Coronal images. Scale bar, 1 mm (center). Magnifications of the areas outlined with white boxes in the coronal images. Scale bar, 200 μm (right). b dVenus-positive cell counts (WT, n = 5; Df/+, n = 4). *P < 0.05, Student’s t test. Data are presented as the mean ± s.e.m.
Fig. 5
Fig. 5
Decreased parvalbumin (PV)-positive cells in the sensory cortex in Df/+ mice. a PV immunostaining showing the decreased number of PV-positive cells in the adult Df/+ mice. Representative figures (left). Scale bar, 100 μm. Quantification of the number of PV-positive cells (each n = 3) (right). *P < 0.05, Student’s t test. b SATB2 immunostaining showing the normal number of SATB2-positive cells in adult Df/+ mice. Representative figures (left). Scale bar, 100 μm. Quantification of the number of SATB2-positive cells (each n = 3) (right). Data are presented as the mean ± s.e.m.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Grove J, Ripke S, Als TD, Mattheisen M, Walters RK, Won H, et al. Identification of common genetic risk variants for autism spectrum disorder. Nat Genet. 2019;51:431–44. doi: 10.1038/s41588-019-0344-8. - DOI - PMC - PubMed
    1. Consortium SWGotPG. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421. doi: 10.1038/nature13595. - DOI - PMC - PubMed
    1. Takata A. Estimating contribution of rare non-coding variants to neuropsychiatric disorders. Psychiat Clin Neurosci. 2019;73:2–10. doi: 10.1111/pcn.12774. - DOI - PubMed
    1. Takumi T, Tamada K. CNV biology in neurodevelopmental disorders. Curr Opin Neurobiol. 2018;48:183–92. doi: 10.1016/j.conb.2017.12.004. - DOI - PubMed
    1. Rutkowski TP, Schroeder JP, Gafford GM, Warren ST, Weinshenker D, Caspary T, et al. Unraveling the genetic architecture of copy number variants associated with schizophrenia and other neuropsychiatric disorders. J Neurosci Res. 2017;95:1144–60. doi: 10.1002/jnr.23970. - DOI - PMC - PubMed

Publication types

Supplementary concepts

LinkOut - more resources