The Acid-Activated Ion Channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory

Abstract

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.

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…ASIC1a is widely expressed in the neurons of peripheral sensory and the central nervous system [13,16,22]. Homomeric ASIC1a channels respond to low pH o by mediating a fast and transient inward current with a threshold pH of ∼7.0, and the pH for half maximal activation (pH 0.5 ) at ∼6.2 [13].…”

“…Although the exact subunit combination and stoichiometry of ASICs in native neurons remain to be determined, the relative contributions by ASIC1a, ASIC2a, or ASIC3 subunit to acidevoked currents in peripheral sensory and CNS neurons have been examined [10,22,23,32]. In medium-sized DRG neurons, for example, acid-activated currents match those recorded from heterologous cells expressing a mix of ASIC1, ASIC2, and ASIC3 subunits [23].…”

“…Deletion of any one subunit did not abolish acid-activated currents, but altered currents in a manner consistent with heteromultimerization of the two remaining subunits, indicating that combinations of two or more ASIC subunits co-assemble as heteromultimeric channels in mouse DRG neurons [23]. In cortical and hippocampal neurons, however, knockout of ASIC1 gene alone almost completely eliminated the acid-activated current [10,22,32], suggesting that ASIC1a is a predominant functional ASIC subunit in CNS neurons. Further studies suggest that the acid-activated currents in CNS neurons are largely mediated by a combination of ASIC1a homomeric channels and ASIC1a/ASIC2a heteromeric channels [32,33].…”

“…For homomeric ASIC1a channels, acid activation also induces Ca 2+ entry directly through these channels [10,12,13]. In addition, the ASIC-mediated membrane depolarization may facilitate the activation of voltage-gated Ca 2+ channels and NMDA receptor-gated channels [22], further promoting neuronal excitation and [Ca 2+ ] i accumulation.…”

“…Additional efforts should focus on the search for new small molecules that specifically blocks the ASIC1a channels. Since activation of ASIC1a is also involved in the processes of learning, memory and fear [22,56], prolonged blockade of these channels in patients may induce some behavior changes.…”