Post-acquisition CO₂ Inhalation Enhances Fear Memory and Depends on ASIC1A

A growing body of evidence suggests that memories of fearful events may be altered after initial acquisition or learning. Although much of this work has been done in rodents using Pavlovian fear conditioning, it may have important implications for fear memories in humans such as in post-traumatic stress disorder (PTSD). A recent study suggested that cued fear memories, made labile by memory retrieval, were made additionally labile and thus more vulnerable to subsequent modification when mice inhaled 10% carbon dioxide (CO₂) during retrieval. In light of this finding, we hypothesized that 10% CO₂ inhalation soon after fear acquisition might affect memory recall 24 h later. We found that both cue and context fear memory were increased by CO₂ exposure after fear acquisition. The effect of CO₂ was time-dependent, as CO₂ inhalation administered 1 or 4 h after cued fear acquisition increased fear memory, whereas CO₂ inhalation 4 h before or 24 h after cued fear acquisition did not increase fear memory. The ability of CO₂ exposure following acquisition to enhance fear memory was not a general consequence of stress, as restraining mice after acquisition did not alter cued fear memory. The memory-enhancing action of CO₂ may be relatively specific to fear conditioning as novel object recognition was impaired by post-training CO₂ inhalation. To explore the molecular underpinnings of these effects, we tested if they depended on the acid-sensing ion channel-1a (ASIC1A), a proton-gated cation channel that mediates other effects of CO₂, likely via its ability to sense acidosis induced during CO₂ inhalation. We found that CO₂ inhalation did not alter cued or context fear memory in Asic1a mice, suggesting that this phenomenon critically depends on ASIC1A. These results suggest that brain acidosis around the time of a traumatic event may enhance memory of the trauma, and may thus constitute an important risk factor for developing PTSD. Moreover, preventing peritraumatic acidosis might reduce risk of PTSD.