Blocking NRSF Function Rescues Spatial Memory Impaired by Early-Life Adversity and Reveals Unexpected Underlying Transcriptional Programs

Adverse early-life experiences are associated with lifelong cognitive deficits and risk of memory loss and dementia, yet the underlying mechanisms remain unclear. Here we imposed early-life adversity by rearing rat pups in simulated poverty, assessed hippocampus-dependent memory in adulthood, and probed enduring changes in gene expression and the underlying transcriptional processes. Adversity-experiencing rats had poor spatial memory, associated with ~130 differentially expressed genes in dorsal hippocampus. Using bioinformatics, we identified the glucocorticoid receptor and, unexpectedly, the neuron-specific developmental transcription factor neuron-restrictive silencer factor (NRSF/REST) as putative upstream factors. To examine the role of the latter in adversity-induced memory problems, we blocked the binding of NRSF to the chromatin immediately following the adversity period. Transient interference with the function of NRSF rescued spatial memory in the exposed rats, without influencing non-hippocampus-dependent emotional functions. These findings establish a novel, surprising mechanism by which early-life adversity initiates long-lasting hippocampus-dependent memory deficits via enduring epigenetic programming mediated by NRSF.