AbstractSATB2 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.
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). Furthermore, similarly to its homologue Satb1 (Wang et al., 2014, 2012), Satb2 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). Moreover, patients with mutations or deletions within the SATB2 locus, a condition referred to as ‘SATB2-associated syndrome (SAS)’, exhibit severe learning difficulties and profound mental retardation, providing further indication for a potential role of SATB2 in higher brain function (Liedén et al., 2014; Zarate et al., 2015; Zarate and Fish, 2016; Marshall et al., 2008). So far the neuropsychiatric symptoms of SAS have been discussed in the context of the established role of Satb2 during embryonic development of the cerebral cortex. In the embryonic cortex Satb2 is restricted to upper layer neurons where it inhibits the corticospinal motor neuron fate and promotes callosal neuron identity (Alcamo et al., 2008; Britanova et al., 2008; Leone et al., 2015; Srinivasan et al., 2012; Srivatsa et al., 2014). Thus, deficits in cortico-cortical connections could account for the reported neurological defects in SAS patients. However, patients with SATB2 haploinsufficiency have no apparent corpus callosum abnormalities (Lee et al., 2015; Rosenfeld et al., 2009). In heterozygous Satb2 knockout mice, resembling the genetic condition of SAS patients, the corpus callosum is also intact (Alcamo et al., 2008). This suggests a function of Satb2 in adult brain independent from its developmental role. The function of Satb2 in the adult central nervous system (CNS) is completely unknown since germ-line Satb2-deficient mice die perinatally (Dobreva et al., 2006). In contrast to the layer-specific embryonic expression, adult CNS Satb2 is expressed in pyramidal neurons of all layers of the cerebral cortex and in the hippocampal CA1 area (Huang et al., 2013). In this study, we investigated the role of Satb2 in the mature mouse brain by selectively deleting Satb2 from forebrain excitatory neurons after the third postnatal week. Our results demonstrate deficient long-term potentiation (LTP) and long-term memory in Satb2 conditional mutants. At a mechanistic level, we establish Satb2 as a nuclear component of two main pathways implicated not only in cognition but also in schizophrenia pathophysiology, i.e. BDNF signaling and miRNA-mediated post-transcriptional regulation of gene expression.