Epigenetic repression of cFos supports sequential formation of distinct spatial memories

Expression of the immediate early gene cFos modifies the epigenetic landscape of activated neurons with downstream effects on synaptic plasticity. The production of cFos is inhibited by a long-lived isoform of another Fos family gene, {Delta}FosB. It has been speculated that this negative feedback mechanism may be critical for protecting episodic memories from being overwritten by new information. Here, we investigate the influence of {Delta}FosB inhibition on cFos expression and memory. Hippocampal neurons in slice culture produce more cFos on the first day of stimulation compared to identical stimulation on the following day. This downregulation affects all hippocampal subfields and requires histone deacetylation. Overexpression of {Delta}FosB in individual pyramidal neurons effectively suppresses cFos, indicating that accumulation of {Delta}FosB is the causal mechanism. Water maze training of mice over several days leads to accumulation of {Delta}FosB in granule cells of the dentate gyrus, but not in CA3 and CA1. Because the dentate gyrus is thought to support pattern separation and cognitive flexibility, we hypothesized that inhibiting the expression of {Delta}FosB would affect reversal learning, i.e., the ability to successively learn new platform locations in the water maze. The results indicate that pharmacological HDAC inhibition, which prevents cFos repression, impairs reversal learning, while learning and memory of the initial platform location remain unaffected. Our study supports the hypothesis that epigenetic mechanisms tightly regulate cFos expression in individual granule cells to orchestrate the formation of time-stamped memories.