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.
Highlights
Satb2 is a transcriptional regulator that binds to matrix attachment regions in the DNA and recruits chromatin-modifying complexes at the anchorage sites (Baranek et al, 2012; Britanova et al, 2005; Gyorgy et al, 2008; Szemes et al, 2006)
The expression of the Camk2a-Cre transgene allowed for a forebrain-specific deletion of Satb2 from the third postnatal week on, bypassing the confounding effects of early Satb2 inactivation on the formation of cortical neuronal circuits (Alcamo et al, 2008; Britanova et al, 2008; Harb et al, 2016; Leone et al, 2015; Srinivasan et al, 2012; Srivatsa et al, 2014)
At molecular level we show in primary hippocampal neurons that calcium influx through L-type VGCC as well as BDNF up-regulate Satb2 in the nucleus, where it binds to promoters of coding and non-coding loci
Summary
Satb is a transcriptional regulator that binds to matrix attachment regions in the DNA and recruits chromatin-modifying complexes at the anchorage sites (Baranek et al, 2012; Britanova et al, 2005; Gyorgy et al, 2008; Szemes et al, 2006). To its homologue Satb (Wang et al, 2014, 2012), Satb modifies higher-order chromatin structure by mediating the formation of intra-chromosomal DNA loops (Zhou et al, 2012). Recent genome-wide association studies of schizophrenia have identified SATB2 as a genetic risk locus (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Patients with mutations or deletions within the SATB2 locus, a condition referred to as ‘SATB2-
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