Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity

Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function. [Display omitted] •Hippocampus-dependent memory is impaired long term by early-life adversity (ELA)•Large-scale repression of key neuronal genes and neuronal stunting are found•Target genes of GR and of the repressor NRSF/REST are enriched•Transient block of NRSF function prevents ELA-induced memory and neuronal deficits Bolton et al. report enduring memory impairments after early-life adversity (ELA) associated with large-scale repression of key hippocampal genes contributing to neuronal maturation and neurotransmission. They identify glucocorticoid receptor (GR) and the repressive transcription factor neuron-restrictive silencer factor (NRSF) as candidate upstream regulators. Temporary block of NRSF chromatin-binding rescues hippocampal memory and neuronal structure.