Acid-sensing ion channel 1a drives AMPA receptor plasticity following ischaemia and acidosis in hippocampal CA1 neurons.

Patrice Quintana,Dominique Muller,Stuart G Cull‐Candy,Olivier Poirot,Roman Chrast,David Soto,Marzieh Zonouzi,Stephan Kellenberger

doi:10.1113/jp270701

Abstract

The hippocampal CA1 region is highly vulnerable to ischaemic stroke. Two forms of AMPA receptor (AMPAR) plasticity - an anoxic form of long-term potentiation and a delayed increase in Ca(2+) -permeable (CP) AMPARs - contribute to this susceptibility by increasing excitotoxicity. In CA1, the acid-sensing ion channel 1a (ASIC1a) is known to facilitate LTP and contribute to ischaemic acidotoxicity. We have examined the role of ASIC1a in AMPAR ischaemic plasticity in organotypic hippocampal slice cultures exposed to oxygen glucose deprivation (a model of ischaemic stroke), and in hippocampal pyramidal neuron cultures exposed to acidosis. We find that ASIC1a activation promotes both forms of AMPAR plasticity and that neuroprotection, by inhibiting ASIC1a, circumvents any further benefit of blocking CP-AMPARs. Our observations establish a new interaction between acidotoxicity and excitotoxicity, and provide insight into the role of ASIC1a and CP-AMPARs in neurodegeneration. Specifically, we propose that ASIC1a activation drives certain post-ischaemic forms of CP-AMPAR plasticity. The CA1 region of the hippocampus is particularly vulnerable to ischaemic damage. While NMDA receptors play a major role in excitotoxicity, it is thought to be exacerbated in this region by two forms of post-ischaemic AMPA receptor (AMPAR) plasticity - namely, anoxic long-term potentiation (a-LTP), and a delayed increase in the prevalence of Ca(2+) -permeable GluA2-lacking AMPARs (CP-AMPARs). The acid-sensing ion channel 1a (ASIC1a), which is expressed in CA1 pyramidal neurons, is also known to contribute to post-ischaemic neuronal death and to physiologically induced LTP. This raises the question does ASIC1a activation drive the post-ischaemic forms of AMPAR plasticity in CA1 pyramidal neurons? We have tested this by examining organotypic hippocampal slice cultures (OHSCs) exposed to oxygen glucose deprivation (OGD), and dissociated cultures of hippocampal pyramidal neurons (HPNs) exposed to low pH (acidosis). We find that both a-LTP and the delayed increase in the prevalence of CP-AMPARs are dependent on ASIC1a activation during ischaemia. Indeed, acidosis alone is sufficient to induce the increase in CP-AMPARs. We also find that inhibition of ASIC1a channels circumvents any potential neuroprotective benefit arising from block of CP-AMPARs. By demonstrating that ASIC1a activation contributes to post-ischaemic AMPAR plasticity, our results identify a functional interaction between acidotoxicity and excitotoxicity in hippocampal CA1 cells, and provide insight into the role of ASIC1a and CP-AMPARs as potential drug targets for neuroprotection. We thus propose that ASIC1a activation can drive certain forms of CP-AMPAR plasticity, and that inhibiting ASIC1a affords neuroprotection.

Highlights

During ischaemia, the excessive release of the excitatory neurotransmitter glutamate leads to neuronal toxicity and death, in part due to over-activation of ligand gated ion channels and the resultant calcium entry
While early work suggested that excitotoxicity due to excessive activation of NMDA receptors (NMDARs) was the main cause of neuronal death in the ischaemic brain, it has become apparent that the situation is more complex, involving activation or alteration of a host of ionotropic receptors and channels (Szydlowska & Tymianski, 2010), including calcium-permeable AMPA receptors (CP-AMPARs) (Pellegrini-Giampietro et al 1992; Opitz et al 2000; Tanaka et al 2002; Noh et al 2005) and acid-sensing ion channels (ASICs) activated by the increased protons associated with ischaemia (Xiong et al 2004; Pignataro et al 2007; Mari et al 2010; Sherwood et al 2011)
Blocking sodium channels with tetrodotoxin (TTX 1 μM) did not inhibit the change (RIpH6+TTX = 0.57 ± 0.06, γpH6+TTX = 22.04 ± 3.10 pS, n = 16, Fig. 4F). These results suggest that modulation of Ca2+-permeable NMDARs and voltage-gated calcium channels (VGCCs) by acid-sensing ion channel 1a (ASIC1a) activation is critical in triggering the observed AMPAR plasticity, suggesting Ca2+ influx is required for the loss of GluA2 expression detected following acidification

Summary

Introduction

The excessive release of the excitatory neurotransmitter glutamate leads to neuronal toxicity and death, in part due to over-activation of ligand gated ion channels and the resultant calcium entry. While early work suggested that excitotoxicity due to excessive activation of NMDA receptors (NMDARs) was the main cause of neuronal death in the ischaemic brain, it has become apparent that the situation is more complex, involving activation or alteration of a host of ionotropic receptors and channels (Szydlowska & Tymianski, 2010), including calcium-permeable AMPA receptors (CP-AMPARs) (Pellegrini-Giampietro et al 1992; Opitz et al 2000; Tanaka et al 2002; Noh et al 2005) and acid-sensing ion channels (ASICs) activated by the increased protons associated with ischaemia (Xiong et al 2004; Pignataro et al 2007; Mari et al 2010; Sherwood et al 2011) How these different membrane channels contribute and interact to confer ischaemic susceptibility is still poorly understood. It is of note that CP-AMPARs are expressed during normal LTP at CA1 synapses in these conditions they are present only transiently (Plant et al 2006; Morita et al 2014; but see Adesnik & Nicoll, 2007)

Methods

Results

Conclusion