Acid-Sensing Ion Channel-1a Is Not Required for Normal Hippocampal LTP and Spatial Memory

Abstract

Acid-sensing ion channel-1a (ASIC1a) is localized in brain regions with high synaptic density and is thought to contribute to synaptic plasticity, learning, and memory. A prominent hypothesis is that activation of postsynaptic ASICs promotes depolarization, thereby augmenting N-methyl-D-aspartate receptor function and contributing to the induction of long-term potentiation (LTP). However, evidence for activation of postsynaptic ASICs during neurotransmission has not been established. Here, we re-examined the role of ASIC1a in LTP in the hippocampus using pharmacological and genetic approaches. Our results showed that a tarantula peptide psalmotoxin, which profoundly blocked ASIC currents in the hippocampal neurons, had no effect on LTP. Similarly, normal LTP was robustly generated in ASIC1a-null mice. A further behavioral analysis showed that mice lacking ASIC1a had normal performance in hippocampusdependent spatial memory. In summary, our results indicate that ASIC1a is not required for hippocampal LTP and spatial memory. We therefore propose that the role of ASIC1a in LTP and spatial learning should be reassessed.

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…If the extracellular Mg 2+ concentration was kept low in these experiments, LTP was normal in ASIC1a knockout animals, suggesting that the ASICmediated postsynaptic depolarization may increase NMDA receptor function by removing the Mg 2+ block. Another study inhibited ASIC1a with Psalmotoxin1 (PcTx1) or used a nervous system-specific ASIC1 knockout approach based on the Cre/Lox system with the Nestin promoter, which leads to the loss of ASIC1 expression at approximately embryonic day 10.5 and, consequently, to the absence of ASIC1a mRNA and ASIC1a currents in brain neurons (Wu et al, 2013). In contrast to previous work with ASIC1a 2/2 mice, Fig.…”

Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala

“…In previous studies of hippocampal brain slices, extracellular field potential recordings suggested impaired hippocampal long-term potentiation (LTP) in ASIC1a −/− mice (20), although another study did not detect an effect of ASIC1a (33). Another study using microisland cultures of hippocampal neurons suggested that the probability of neurotransmitter release increased in ASIC1a −/− mice (32).…”

Acid-sensing ion channel (ASIC) 1a/2a heteromers have a flexible 2:1/1:2 stoichiometry

“…ASICs in central neurons are mainly composed of homomeric ASIC1a and heteromeric ASIC1a/2a (3)(4)(5)(6) and ASIC1a/2b (7). Genetic ablation of ASIC1a has indeed led to the conclusion that ASICs contribute to long-term potentiation and memory formation (2), but a more recent study challenged these findings (8). In contrast to our incomplete understanding of the physiological functions of ASICs, there is a comparatively large body of evidence that activation of ASIC1a-containing channels in pathophysiological states that are associated with sustained acidosis contributes to neuronal or axonal degeneration (9,10).…”