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

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-CreSatb2 mice), and adult Satb2 ablation mice (Satb2 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-CreSatb2 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.

Mutation update for the SATB2 gene

“…In general, Satb2 functions as a transcriptional regulator that is important for tissue‐specific functions. In mice bone progenitors, Satb2 regulates osteogenic differentiation genes (Dobreva et al, ), while in postmitotic neurons Satb2 regulates expression of genes involved in upper layer identity, synaptic transmission, and axon guidance (Jaitner et al, ; Li et al, ; Whitton et al, ). The consequence of loss of Satb2 in bone progenitors is reduced bone size and density due to increased cell death and reduced differentiation potential (Britanova et al, ; Dobreva et al, ).…”

“…In murine brain development, Satb2 is required to specify upper layer cortical neurons that project axons across the corpus callosum to the contralateral hemisphere (Alcamo et al, ; Britanova et al, ). Loss of Satb2 also results in reduced branches and spine density in basal dendrites of hippocampal neurons (Li et al, ). Similar to patients with SAS, Satb2 +/‐ heterozygous mice have no reported corpus callosum defects (Alcamo et al, ; Zarate, Smith‐Hicks et al ()).…”

“…However, Satb2 +/‐ heterozygous mice suffer from impaired working and spatial memory. This deficit is exacerbated in mice where Satb2 has been deleted postnatally in hippocampal neurons (Li et al, ). These mice also have difficulties in locomotion, short‐term novel object recognition memory, and long‐term contextual fear memory (Jaitner et al, ; Li et al, ).…”

Satb2 is required for the regionalization of retrosplenial cortex

“…While postnatally, Satb2 is required for proper dendritic and soma adhesion of callosal neurons in neocortex [32]. In adult, Satb2 deletion leads to impairment in long-term memory [33,34]. We also reported that mice with loss of Satb2 in cortex and hippocampus show hyperactivity, increased impulsivity, abnormal social novelty, and impaired spatial learning and memory [35].…”

The gut microbiota regulates autism-like behavior by mediating vitamin B6 homeostasis in EphB6-deficient mice

“…Then posterior mPFC and VTA were sectioned out using ice-cold mouse brain mold (Cat# 68713, RWD). qRT-PCR was performed accordingly [54] by using a 7500 real-time PCR system (ABI, California, USA) and SYBR Premix Ex Taq (Cat# RR420A, Takara, Osaka, Japan). Normalized to the mRNA expression level of Gapdh or Actb, the mRNA expression of other genes was evaluated using the method of ΔΔCt.…”