Abstract
22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by the segmental deletion of human chromosome 22. This chromosomal deletion is known as high genetic risk factors for various psychiatric disorders. The different deletion types are identified in 22q11.2DS patients, including the most common 3.0-Mb deletion, and the less-frequent 1.5-Mb and 1.4-Mb deletions. In previous animal studies of psychiatric disorders associated with 22q11.2DS mainly focused on the 1.5-Mb deletion and model mice mimicking the human 1.5-Mb deletion have been established with diverse genetic backgrounds, which resulted in the contradictory phenotypes. On the other hand, the contribution of the genes in 1.4-Mb region to psychiatric disorders is poorly understood. In this study, we generated two mouse lines that reproduced the 1.4-Mb and 1.5-Mb deletions of 22q11.2DS [Del(1.4 Mb)/+ and Del(1.5 Mb)/+] on the pure C57BL/6N genetic background. These mutant mice were analyzed comprehensively by behavioral tests, such as measurement of locomotor activity, sociability, prepulse inhibition and fear-conditioning memory. Del(1.4 Mb)/+ mice displayed decreased locomotor activity, but no abnormalities were observed in all other behavioral tests. Del(1.5 Mb)/+ mice showed reduction of prepulse inhibition and impairment of contextual- and cued-dependent fear memory, which is consistent with previous reports. Furthermore, apparently intact social recognition in Del(1.4 Mb)/+ and Del(1.5 Mb)/+ mice suggests that the impaired social recognition observed in Del(3.0 Mb)/+ mice mimicking the human 3.0-Mb deletion requires mutations both in 1.4-Mb and 1.5 Mb regions. Our previous study has shown that Del(3.0 Mb)/+ mice presented disturbance of behavioral circadian rhythm. Therefore, we further evaluated sleep/wakefulness cycles in Del(3.0 Mb)/+ mice by electroencephalogram (EEG) and electromyogram (EMG) recording. EEG/EMG analysis revealed the disturbed wakefulness and non-rapid eye moving sleep (NREMS) cycles in Del(3.0 Mb)/+ mice, suggesting that Del(3.0 Mb)/+ mice may be unable to maintain their wakefulness. Together, our mouse models deepen our understanding of genetic contributions to schizophrenic phenotypes related to 22q11.2DS.
Highlights
The 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder in humans, with an estimated incidence of 1 in 1000–4000 live births [1,2,3]
The most frequent 3.0-Mb deletion is caused by non-allelic homologous recombination (NAHR) between LCR22A and LCR22D, and the 1.5-Mb deletion and 1.4-Mb deletion are caused by NAHR between LCR22A and B and between LCR22B and D, respectively [12,13,14]
To introduce the deletion between Phosphatidylinositol 4-kinase alpha (Pi4ka) and DiGeorge syndrome critical region 2 (Dgcr2) on mouse chromosome 16, we designed a pair of Single-guide ribonucleic acid (sgRNA) on each target locus of Pi4ka intron 47 and Dgcr2
Summary
The 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal microdeletion disorder in humans, with an estimated incidence of 1 in 1000–4000 live births [1,2,3]. The contributions of the genes located on the remaining 1.4-Mb region (LCR22B–D in 1.4-Mb deletion) to this syndrome are poorly understood This 1.4-Mb deletion is included in 3.0-Mb deletion of Del(3.0 Mb)/+ mouse model mimicking the most common 3.0-Mb deletion in the human 22q11.2 locus, the influence of 1.4-Mb deletion alone on psychiatric phenotypes has not been studied in this model [19]. Individuals with this 1.4-Mb deletion including LCR22B–D and LCR22C–D deletion have been diagnosed as ADHD, anxiety disorder, developmental delay and intellectual disability [6]. We evaluated the rescuing effects of the anti-psychotic drug on the reduced PPI and sleep/wakefulness cycles related to circadian rhythm using Del(3.0 Mb)/+ mice
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