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ASIC1A in neurons is critical for fear-related behaviors.

ABSTRACT: Acid-sensing ion channels (ASICs) have been implicated in fear-, addiction- and depression-related behaviors in mice. While these effects have been attributed to ASIC1A in neurons, it has been reported that ASICs may also function in nonneuronal cells. To determine if ASIC1A in neurons is indeed required, we generated neuron-specific knockout (KO) mice with floxed Asic1a alleles disrupted by Cre recombinase driven by the neuron-specific synapsin I promoter (SynAsic1a KO mice). We confirmed that Cre expression occurred in neurons, but not all neurons, and not in nonneuronal cells including astrocytes. Consequent loss of ASIC1A in some but not all neurons was verified by western blotting, immunohistochemistry and electrophysiology. We found ASIC1A was disrupted in fear circuit neurons, and SynAsic1a KO mice exhibited prominent deficits in multiple fear-related behaviors including Pavlovian fear conditioning to cue and context, predator odor-evoked freezing and freezing responses to carbon dioxide inhalation. In contrast, in the nucleus accumbens ASIC1A expression was relatively normal in SynAsic1a KO mice, and consistent with this observation, cocaine conditioned place preference (CPP) was normal. Interestingly, depression-related behavior in the forced swim test, which has been previously linked to ASIC1A in the amygdala, was also normal. Together, these data suggest neurons are an important site of ASIC1A action in fear-related behaviors, whereas other behaviors likely depend on ASIC1A in other neurons or cell types not targeted in SynAsic1a KO mice. These findings highlight the need for further work to discern the roles of ASICs in specific cell types and brain sites.

SUBMITTER: Taugher RJ

PROVIDER: S-EPMC5677554 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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ASIC1A in neurons is critical for fear-related behaviors.

Taugher R J RJ Lu Y Y Fan R R Ghobbeh A A Kreple C J CJ Faraci F M FM Wemmie J A JA

Genes, brain, and behavior 20170721 8

Acid-sensing ion channels (ASICs) have been implicated in fear-, addiction- and depression-related behaviors in mice. While these effects have been attributed to ASIC1A in neurons, it has been reported that ASICs may also function in nonneuronal cells. To determine if ASIC1A in neurons is indeed required, we generated neuron-specific knockout (KO) mice with floxed Asic1a alleles disrupted by Cre recombinase driven by the neuron-specific synapsin I promoter (SynAsic1a KO mice). We confirmed that ...[more]

PMID: 28657172

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Project description: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.

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ASIC1A in neurons is critical for fear-related behaviors.

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ASIC1A in neurons is critical for fear-related behaviors.

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