Satb2 determines miRNA expression and long-term memory in the adult central nervous system

Abstract

SATB2 is a risk locus for schizophrenia and encodes a DNA-binding protein that regulates higher-order chromatin configuration. In the adult brain Satb2 is almost exclusively expressed in pyramidal neurons of two brain regions important for memory formation, the cerebral cortex and the CA1-hippocampal field. Here we show that Satb2 is required for key hippocampal functions since deletion of Satb2 from the adult mouse forebrain prevents the stabilization of synaptic long-term potentiation and markedly impairs long-term fear and object discrimination memory. At the molecular level, we find that synaptic activity and BDNF up-regulate Satb2, which itself binds to the promoters of coding and non-coding genes. Satb2 controls the hippocampal levels of a large cohort of miRNAs, many of which are implicated in synaptic plasticity and memory formation. Together, our findings demonstrate that Satb2 is critically involved in long-term plasticity processes in the adult forebrain that underlie the consolidation and stabilization of context-linked memory.DOI: http://dx.doi.org/10.7554/eLife.17361.001

Natural history and genotype‐phenotype correlations in 72 individuals with SATB2‐associated syndrome

“…SAS is a multi‐system disorder caused by alterations of the SATB2 gene, a transcription factor that binds to nuclear matrix‐attachment regions (MARs) and activates the transcription of genes that are critical to the development of multiple organ systems, tissues, including the jaw, brain, and skeleton (Britanova et al, ; Dobreva et al, ; Dobreva, Dambacher, & Grosschedl, ; Gyorgy, Szemes, de Juan Romero, Tarabykin, & Agoston, ; Jaitner et al, ). In this manuscript we provide the basis to better characterize the natural history and assess genotype‐phenotype correlations.…”

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].…”

“…Recently, we found that emotional behavior and spatial learning and memory were impaired in Satb2 CKO mice [35]. Rsp-or CA1-specific Cre is needed to exclusively delete Satb2 for elucidating its function in these regions, which will promote our understanding of how Satb2 is involved in neurodevelopmental diseases and psychiatric disorders [33].…”

Genes Involved in Long-Term Memory Are Expressed in Testis of Cryptorchid Boys and Respond to GnRHa Treatment

“…Based on the highly specific expression pattern of SATB2 in the adult brain and the severe learning disabilities and mental retardation observed in patients diagnosed with SAS (SATB2-associated syndrome), it was hypothesized that SATB2 is critical for human learning and memory [Jaitner et al, 2016]. Interestingly, while SATB2 showed no post-treatment response, its lncRNA, SATB2 antisense, did respond to GnRHa treatment (+1.78 logFC, FDR 0.019).…”

“…Interestingly, while SATB2 showed no post-treatment response, its lncRNA, SATB2 antisense, did respond to GnRHa treatment (+1.78 logFC, FDR 0.019). At the molecular level, BDNF upregulates SATB2 , which itself binds to promoters of coding and noncoding genes [Jaitner et al, 2016]. It was recently shown that the MSI (Musashi) gene induces forgetting and represents a novel mechanism of memory decay by linking translational control to the structure of the neuronal actin cytoskeleton .…”