Acid-sensing ion channel 1a contributes to hippocampal LTP inducibility through multiple mechanisms

Abstract

The exact roles of acid-sensing ion channels (ASICs) in synaptic plasticity remain elusive. Here, we address the contribution of ASIC1a to five forms of synaptic plasticity in the mouse hippocampus using an in vitro multi-electrode array recording system. We found that genetic deletion or pharmacological blockade of ASIC1a greatly reduced, but did not fully abolish, the probability of long-term potentiation (LTP) induction by either single or repeated high frequency stimulation or theta burst stimulation in the CA1 region. However, these treatments did not affect hippocampal long-term depression induced by low frequency electrical stimulation or (RS)-3,5-dihydroxyphenylglycine. We also show that ASIC1a exerts its action in hippocampal LTP through multiple mechanisms that include but are not limited to augmentation of NMDA receptor function. Taken together, these results reveal new insights into the role of ASIC1a in hippocampal synaptic plasticity and the underlying mechanisms. This unbiased study also demonstrates a novel and objective way to assay synaptic plasticity mechanisms in the brain.

ASIC1a regulates insular long-term depression and is required for the extinction of conditioned taste aversion

“…The role of ASIC1a in insular LTD was unexpected because in other brain regions, ASIC1a has been shown to be important for LTP6172021. This disparity probably reflects the cognitive demand-dependent distinct eligibility traces53 for LTD or LTP in different synapses.…”

“…Given its postsynaptic localization616, ASIC1a has been postulated to be activated by synaptically released protons during normal neurotransmission1718. ASIC1a serves as the main synaptic proton receptor to regulate high-frequency stimulation or theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampus61920 and amygdala1721, and contribute to fear learning141621. ASIC1a promotes spine density in hippocampus22, but inhibits spine density, alters the excitatory synaptic receptor function and constrains cocaine-evoked plasticity in nucleus accumbens18, suggesting complex roles of ASIC1a in modulating synaptic plasticity and behavioural adaptation.…”

Acid-sensing ion channel 1a is required for mGlu receptor dependent long-term depression in the hippocampus

“…In fact, it has been suggested that ASIC1a may contribute to certain forms of synaptic plasticity in the hippocampus, although results are controversial [8,17,18]. Here we show for the first time that ASIC1a plays a critical role in mGlu receptordependent LTD of AMPA receptor-mediated transmission in CA1 pyramidal neurons of early adult mice.…”

“…The difference between this and our study might rely on experimental variables including electrophysiological approach used (multielectrode array vs. patch-clamp recordings); animal age (>40 days old vs. ≤P40 days old); temperature (30 • C vs. 28 • C) concentration of PcTx1 (100 nM vs. 100 ng/ml); and use of different enantiomer, concentration (100 M vs. 50 M) and time of perfusion (20 min vs. 10 min) of DHPG. Finally, differently from Liu and colleagues [18], we have investigated different components of excitatory transmission following the pharmacological isolation of NMDA or AMPA receptor component. In agreement with this, experiments showing the contribution of ASIC1a to mGlu-LTD have been observed only in early adult mice, a time in which a post-synaptic mechanism of expression of mGlu-LTD in mature spines has been suggested [40].…”

“…It has been demonstrated that ASICs are required for long-term potentiation (LTP) at cortico-basal lateral amygdala synapses, and are critical for associative fear learning and memory [16]. On the other hand, the role of ASICs in the hippocampus is still not clear [8,13,17,18] and may vary depending on the experimental conditions used. Recently, it was demonstrated that ASICs activity is potentiated by group I mGlu receptors in the peripheral nervous system [19].…”