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Satb2 Ablation Impairs Hippocampus-Based Long-Term Spatial Memory and Short-Term Working Memory and Immediate Early Genes (IEGs)-Mediated Hippocampal Synaptic Plasticity

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Abstract

Special AT-rich sequence-binding protein 2 (Satb2) is a protein binding to the matrix attachment regions of DNA and important for gene regulation. Patients with SATB2 mutation usually suffer moderate to severe mental retardation. However, the mechanisms for the defects of intellectual activities in patients with SATB2 mutation are largely unclear. Here we established the heterozygous Satb2 mutant mice and Satb2 conditional knockout mice to mimic the patients with SATB2 mutation and figured out the role of Satb2 in mental activities. We found that the spatial memory and working memory were significantly damaged in the heterozygous Satb2 mutant mice, early postnatal Satb2-deficient mice (CaMKIIα-Cre+Satb2fl/fl mice), and adult Satb2 ablation mice (Satb2fl/fl mice injected with CaMKIIα-Cre virus). Functionally, late phase long-term potentiation (L-LTP) in these Satb2 mutant mice was greatly impaired. Morphologically, in CA1 neurons of CaMKIIα-Cre+Satb2fl/fl mice, we found decreased spine density of the basal dendrites and less branches of apical dendrites that extended into lacunar molecular layer. Mechanistically, expression levels of immediate early genes (IEGs) including Fos, FosB, and Egr1 were significantly decreased after Satb2 deletion. And, Satb2 could regulate expression of FosB by binding to the promoter of FosB directly. In general, our study uncovers that Satb2 plays an important role in spatial memory and working memory by regulating IEGs-mediated hippocampal synaptic plasticity.

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Authors and Affiliations

  1. Department of Pathology, Sun Yat-Sen Memorial Hospital, Guangzhou, 510120, People’s Republic of China

    Ying Li & Jian-Ming Li

  2. Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People’s Republic of China

    Ying Li, Yu-Ying Hu & Jian-Ming Li

  3. Department of Pathology, Chancheng Central Hospital, Foshan, 528031, People’s Republic of China

    Ying Li

  4. State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China

    Qiang-Long You, Sheng-Rong Zhang, Wei-Yuan Huang, Wen-Jun Zou, Wei Jie, Shu-Ji Li, Ji-Hong Liu, Jin Cong & Tian-Ming Gao

  5. College of Clinical Medical, Southern Medical University, Guangzhou, 510515, People’s Republic of China

    Chuang-Ye Lv

  6. Department of Pathology, Soochow University Medical School, Suzhou, 215123, People’s Republic of China

    Jian-Ming Li

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Contributions

Ying-Li, Tian-Ming Gao, and Jian-Ming Li contributed to study concept and design; Ying-Li, Qiang-Long You, Sheng-Rong Zhang, Wei-Yuan Huang, Wen-Jun Zou, Wei Jie, Shu-Ji Li, Ji-Hong Liu, Chuang-Ye Lv, Jin Cong, and Yu-Ying Hu contributed to data acquisition; Ying-Li, Tian-Ming Gao, and Jian-Ming Li contributed to data analysis and interpretation; Ying-Li, Tian-Ming Gao, and Jian-Ming Li contributed to manuscript drafting; Tian-Ming Gao and Jian-Ming Li contributed to funding obtaining and study supervision.

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Correspondence to Tian-Ming Gao or Jian-Ming Li.

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This work was supported by the National Nature Science Foundation of China (Grants 81,525,020, 81,502,033, 81,272,300, 31570753, 31430032 and U1201225).

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The authors declare that they have no conflicts of interest.

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Fig. S1

Heterozygous Satb2 mutant mice show normal locomotor activity and fear memory. (A and B) Open field test. Distance traveled (A) and time in center (B) for Satb2+/+ mice (n = 16) and Satb2+/− mice (n = 14) in 30 min. (C) Novel object recognition test. Satb2+/+ mice (n = 15) and Satb2+/− mice (n = 20) had similar preference to the novel object at 1 h after memorizing the circumstance and old objects. (D and E) Contextual fear conditioning. Similar freezing time of Satb2+/+ mice (n = 9) and Satb2+/− mice (n = 10) was showed during fear-acquisition period (D). After 24 h, intact contextual fear memory of Satb2+/− mice was showed in memory retrieval phase (E). (F) Y-maze. Correct trials of Satb2+/− mice (n = 15) were similar with Satb2+/+ mice (n = 16) during spontaneous exploration in Y-shaped apparatus. Data shown are represented as mean ± SEM. *P < 0.05. **P < 0.01. ***P < 0.001. (DOCX 219 kb)

Fig. S2

Heterozygous deletion of Satb2 in mice leads to impaired social memory. (A) Self-grooming time for Satb2+/+ mice (n = 17) and Satb2+/− mice (n = 15) was similar in 10 min. (B–F) Three-chambered social test. Three divided chambers were named left, middle, and right ones. During the first 10-min habituation phase, time spent in left and right chambers was close both in Satb2+/+ mice (n = 14) and Satb2+/− mice (n = 12) (B). During the second 10-min phase, time spent in left chamber with stranger 1 was higher than right chamber with an empty box both in Satb2+/+ mice and Satb2+/− mice (C) and the sniffing time spent on stranger 1 was also higher than that on the empty box (D). During the third 10-min phase, time spent in left chamber with stranger 1 and right chamber with stranger 2 were similar in Satb2+/− mice (E), and Satb2+/− mice also did not show an increase in the sniffing time spent on stranger 2 (F). Data shown are represented as mean ± SEM. *P < 0.05. **P < 0.01. ***P < 0.001. (DOCX 268 kb)

Fig. S3

Hyperactivity and aberrant prefrontal cortex are showed when the expression of Satb2 in pyramidal neurons is deleted in mice. (A and B) Open field test. Distance traveled (A) and time in center (B) for Satb2fl/fl mice and Cre+Satb2fl/fl mice in 30 min. Cre+Satb2fl/fl mice showed increased locomotor activities (A) and increased time in center (B). (C) Anti-Neun antibody was used to incubate prefrontal cortex slices of Satb2fl/fl mice and Cre+Satb2fl/fl mice. The green fluorescence represented Neun positive cells. The white boxes with dotted lines showed the aberrant neuronal distributions in Cre+Satb2fl/fl mice. Data shown are represented as mean ± SEM. *P < 0.05. **P < 0.01. ***P < 0.001. (DOCX 756 kb)

Fig. S4

Satb2 regulates FosB directly in the hippocampus of mice. (A–C) ChIP-PCR assay was used to find out the genomic binding sites for Fos (A), FosB (B), and Egr2 (C). ChIP was carried out with either anti-Satb2 antibody or anti-RNA pol II antibody or anti-IgG antibody. Predicted Satb2-binding loci are marked by red squares under the genomic sequence. Exons for each genomic sequence are marked by green boxes and translation initiation sites are marked by black arrows. Satb2 could bind with FosB on the site numbered 1. (DOCX 215 kb)

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Li, Y., You, QL., Zhang, SR. et al. Satb2 Ablation Impairs Hippocampus-Based Long-Term Spatial Memory and Short-Term Working Memory and Immediate Early Genes (IEGs)-Mediated Hippocampal Synaptic Plasticity. Mol Neurobiol (2017). https://doi.org/10.1007/s12035-017-0531-5

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