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The genetic and molecular basis underlying fear memory formation is a key theme in anxiety disorder research. Because activating transcription factor 3 (ATF3) is induced under stress conditions and is highly expressed in the hippocampus, we hypothesize that ATF3 plays a role in fear memory formation. We used fear conditioning and various other paradigms to test Atf3 knockout mice and study the role of ATF3 in processing fear memory. The results demonstrated that the lack of ATF3 specifically enhanced the expression of fear memory, which was indicated by a higher incidence of the freeze response after fear conditioning, whereas the occurrence of spatial memory including Morris Water Maze and radial arm maze remained unchanged. The enhanced freezing behavior and normal spatial memory of the Atf3 knockout mice resembles the fear response and numbing symptoms often exhibited by patients affected with posttraumatic stress disorder. Additionally, we determined that after fear conditioning, dendritic spine density was increased, and expression of Gelsolin, the gene encoding a severing protein for actin polymerization, was down-regulated in the bilateral hippocampi of the Atf3 knockout mice. Taken together, our results suggest that ATF3 may suppress fear memory formation in mice directly or indirectly through mechanisms involving modulation of actin polymerization.

Memory retrieval dysfunction is a symptom of schizophrenia, autism spectrum disorder (ASD), and absence epilepsy (AE), as well as an early sign of Alzheimer’s disease. To date, few drugs have been reported to enhance memory retrieval. Here, we found that a coral-derived natural product, excavatolide-B (Exc-B), enhances contextual memory retrieval in both wild-type and Cav3.2−/− mice via repressing the delayed rectifier potassium current, thus lowering the threshold for action potential initiation and enhancing induction of long-term potentiation (LTP). The human CACNA1H gene encodes a T-type calcium channel (Cav3.2), and its mutation is associated with schizophrenia, ASD, and AE, which are all characterized by abnormal memory function. Our previous publication demonstrated that Cav3.2−/− mice exhibit impaired contextual-associated memory retrieval, whilst their retrieval of spatial memory and auditory cued memory remain intact. The effect of Exc-B on enhancing the retrieval of context-associated memory provides a hope for novel drug development.