Activity-dependent increase of Egr1 in the hippocampus improves contextual memory in mice

The immediate early gene transcription factor Early growth response 1 ( Egr1 ) is expressed in neurons in response to neuronal activity and plays an essential role in encoding memory of the events that triggered its expression. Mice lacking Egr1 have deficits in hippocampal long-term potentiation and long-term memory. These findings suggest that increasing levels of Egr1 may improve memory. However, typical methods to augment gene expression fail to replicate the activity-responsive timing and location of Egr1 expression, which may disrupt the unique pattern of activated neurons essential for forming the memory engram. To address this problem, we have created an adeno-associated virus (AAV) that expresses Egr1 under control of an activity-dependent promoter containing the enhanced synaptic activity response element (ESARE), which incorporates multiple copies of SARE isolated from the gene activity regulated cytoskeleton associated protein ( Arc ). Infusion of AAV-ESARE- Egr1 into the mouse dentate gyrus produces activity-inducible expression and increases EGR1 immunofluorescence in active hippocampal DG cells by 2.8- to 9.6-fold in response to neuronal stimulation. Mice expressing AAV-ESARE- Egr1 in the DG bilaterally demonstrate recall 24 hours following a one-minute exposure to a novel context, while control-virus injected animals fail to show recognition following this brief exposure. AAV-ESARE- Egr1 injected mice show enhanced memory in contextual fear conditioning, compared with controls. Increasing activity-dependent Egr1 expression in hippocampal DG cells enhances contextual memory in mice, suggesting that developing molecules which can upregulate Egr1 in response to neuronal activity may have therapeutic use in disorders characterized by memory deficits.