Many central neurons possess large acid-activated currents, yet their molecular identity is unknown. We found that eliminating the acid sensing ion channel (ASIC) abolished H(+)-gated currents in hippocampal neurons. Neuronal H(+)-gated currents and transient acidification are proposed to play a role in synaptic transmission. Investigating this possibility, we found ASIC in hippocampus, in synaptosomes, and in dendrites localized at synapses. Moreover, loss of ASIC impaired hippocampal long-term potentiation. ASIC null mice had reduced excitatory postsynaptic potentials and NMDA receptor activation during high-frequency stimulation. Consistent with these findings, null mice displayed defective spatial learning and eyeblink conditioning. These results identify ASIC as a key component of acid-activated currents and implicate these currents in processes underlying synaptic plasticity, learning, and memory.

The acid-sensing ion channel, ASIC1, contributes to synaptic plasticity in the hippocampus and to hippocampus-dependent spatial memory. To explore the role of ASIC1 in brain, we examined the distribution of ASIC1 protein. Surprisingly, although ASIC1 was present in the hippocampal circuit, it was much more abundant in several areas outside the hippocampus. ASIC1 was enriched in areas with strong excitatory synaptic input such as the glomerulus of the olfactory bulb, whisker barrel cortex, cingulate cortex, striatum, nucleus accumbens, amygdala, and cerebellar cortex. Because ASIC1 levels were particularly high in the amygdala, we focused further on this area. We found that extracellular acidosis elicited a greater current density in amygdala neurons than hippocampal neurons and that disrupting the ASIC1 gene eliminated H+-evoked currents in the amygdala. We also tested the effect of ASIC1 on amygdala-dependent behavior; ASIC1-null mice displayed deficits in cue and context fear conditioning, yet baseline fear on the elevated plus maze was intact. These studies suggest that ASIC1 is distributed to regions supporting high levels of synaptic plasticity and contributes to the neural mechanisms of fear conditioning.

The acid-sensing ion channel 1a (ASIC1a) is abundantly expressed in the amygdala complex and other brain regions associated with fear. Studies of mice with a disrupted ASIC1 gene suggested that ASIC1a may contribute to learned fear. To test this hypothesis, we generated mice overexpressing human ASIC1a by using the panneuronal synapsin 1 promoter. Transgenic ASIC1a interacted with endogenous mouse ASIC1a and was distributed to the synaptosomal fraction of brain. Transgenic expression of ASIC1a also doubled neuronal acid-evoked cation currents. The amygdala showed prominent expression, and overexpressing ASIC1a enhanced fear conditioning, an animal model of acquired anxiety. These data raise the possibility that ASIC1a and H ؉ -gated currents may contribute to the development of abnormal fear and to anxiety disorders in humans.