Abstract
Established fear memory becomes vulnerable to disruption after memory retrieval and extinction; this labile state is critical for inhibiting the return of fear memory. However, the labile state has a very narrow time window after retrieval, and underlying molecular mechanisms are not well known. To that end, we isolated the hippocampus immediately after fear memory retrieval and performed proteomics. We identified Neurobeachin (NBEA), an autism-related regulator of synaptic protein trafficking, to be upregulated after contextual fear memory retrieval. NBEA protein expression was rapid and transient after fear memory retrieval at the synapse. Nbea mRNA was enriched at the synapses, and the rapid induction of NBEA expression was blocked by inhibition of the mammalian target of rapamycin (mTOR)-dependent signaling pathway. Mice with cornu ammonis 1 (CA1)-specific Nbea shRNA knockdown showed normal fear acquisition and contextual fear memory but impaired extinction, suggesting an important role of Nbea in fear memory extinction processes. Consistently, Nbea heterozygotes showed normal fear acquisition and fear memory recall but showed impairment in extinction. Our data suggest that NBEA is necessary either for induction of memory lability or for the physiological process of memory extinction.
Highlights
Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder developed from exposure to severe traumatic events[1]
Among the 14 regulated proteins identified in the proteomic analysis, we decided to focus on the role of NBEA in the fear memory process because NBEA is known to regulate synaptic transmission by modulating the trafficking of receptors, including amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, at synapses[12,13,20]
Since we focused on the rapid induction of protein expression and given the major role of NBEA in trafficking neurotransmitter receptors, we isolated synaptosomes from the dorsal hippocampus to examine the specific role of NBEA at the synapse
Summary
Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder developed from exposure to severe traumatic events[1]. Fear memory retrieval renders the original memory labile, allowing a short time window for amnesic intervention. De novo protein synthesis has been shown to be involved in extinction[5] and memory lability to trigger instability of the original memory[6,7]. A memory-labile state is rapidly established after retrieval and has a very narrow time window[8]. Which molecules are rapidly expressed after fear memory retrieval and the roles of these newly synthesized proteins in memory susceptibility and extinction have not been studied. There are insufficient studies to identify the link between the molecular role of NBEA and the resulting behavioral phenotypes, especially fear memory processes. We performed unbiased proteomics to isolate the molecules involved in fear memory retrieval and found that NBEA was upregulated in the dorsal hippocampus. Suppression of NBEA expression by knockdown and knockout impaired extinction, suggesting that NBEA is necessary for either the induction of memory lability or the physiological process of memory extinction
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