Targeting ASIC1a reduces innate fear and alters neuronal activity in the fear circuit

Background: The molecular mechanisms underlying innate fear are poorly understood. Previous studies indicated that the acid sensing ion channel ASIC1 a influences fear behavior in conditioning paradigms. However,these differences may have resulted from an ASIC1 a effect on learning, memory, or the expression of fear. Methods: To test the hypothesis that ASIC1a influences the expression of fear or anxiety independent of classical conditioning, we examined the effects of disrupting the mouse ASIC1a gene on unconditioned fear in the open field test, unconditioned acoustic startle, and fear evoked by the predator odor trimethylthiazoline (TMT). In addition, we tested the effects of acutely inhibiting ASIC1 a with PcTx, an ASIC1a antagonist in tarantula venom. Our immunohistochemistry suggested ASIC1a is expressed in the bed nucleus of the stria terminalis, medial amygdala, and periaqueductal gray, which are thought to play important roles in the generation and expression of innate fear. Therefore, we also tested whether ASIC1 a disruption altered c-fos expression in these structures following TMT exposure. Results: We found that the loss of ASIC1 a reduced fear in the open field test, reduced acoustic startle, and inhibited the fear response to TMT. Similarly, intracerebroventricular administration of PcTx reduced TMT-evoked freezing in ASIC1a(+/+) mice but not ASIC1a(-/-) mice. In addition, loss of ASIC1 a altered TMT-evoked c-fos expression in the medial amydala and dorsal periaqueductal gray. Conclusions: These findings suggest that ASIC1 a modulates activity in the circuits underlying innate fear. Furthermore, the data indicate that targeting the ASIC1a gene or acutely inhibiting ASIC1 a suppresses fear and anxiety independent of conditioning.