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 non-neuronal cells. To determine if ASIC1A in neurons is indeed required, we generated neuron-specific knockout 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 non-neuronal 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.

A novel role for acid‐sensing ion channels in Pavlovian reward conditioning

“…whereas others have not observed vision-based abnormalities that would disrupt detection of visual cues in our experiments 28. For example, in fear conditioning, the CS was 20 seconds (auditory tone) or continuous (context), and the footshock (US) was only 1 second 4,19,20. The results here suggest that altering the timing of the CS-US relationship might influence the outcomes in those other paradigms.…”

“…5,7,[13][14][15] Effects of ASIC1A disruption on dendritic spine density and glutamate receptor composition and function have been reported, 7,13,15,16 as well as effects on long-term potentiation 5,7,17 and long-term depression. 4,6,[17][18][19][20] These deficits were reproduced with amygdalaspecific ASIC1A disruption, 17 and a deficit in contextual fear memory was rescued by expressing ASIC1A in the amygdala. Consistent with the above observations, effects of ASIC1A on Pavlovian conditioning to aversive stimuli have been described.…”

“…13 These results suggest that ASIC1A reduces conditioning to drug rewards. 4,6,[17][18][19][20] Thus, ASIC1A may have differential effects depending on whether the US is rewarding or aversive, although more study is needed to test this possibility. 4,6,[17][18][19][20] Thus, ASIC1A may have differential effects depending on whether the US is rewarding or aversive, although more study is needed to test this possibility.…”

Interpreting Neuroendocrine Hormones, Corticosterone, and Blood Glucose to Assess the Wellbeing of Anesthetized Rats during Euthanasia

“…For example, acid-sensing ion channel 1a (ASIC1a) is recognized to contribute to the development of fear behaviors. 22,23,25 Therefore, the observed increases in the rats' serum ACTH and noradrenaline levels were expected. However, the significant increase in the ACTH concentration of male rats compared with females was surprising, given that previous work suggested that females generally demonstrate higher increases in response to stress.…”

Neurophysiological and neuropsychological damages produced by cocaine in adult populations

“…This depression causes that they begin to produce addictive behaviors and force the consumer to look for contexts of easy access to this type of illegal drugs. 4 …”