Key points 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 Ca2+‐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. AbstractThe 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 Ca2+‐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.

Mitochondria are critical for the function and maintenance of myelinated axons notably through Adenosine triphosphate (ATP) production. A direct by-product of this ATP production is reactive oxygen species (ROS), which are highly deleterious for neurons. While ATP shortage and ROS levels increase are involved in several neurodegenerative diseases, it is still unclear whether the real-time dynamics of both ATP and ROS production in axonal mitochondria are altered by axonal or demyelinating neuropathies. To answer this question, we imaged and quantified mitochondrial ATP and hydrogen peroxide (H 2 O 2 ) in resting or stimulated peripheral nerve myelinated axons in vivo , using genetically-encoded fluorescent probes, two-photon time-lapse and CARS imaging. We found that ATP and H 2 O 2 productions are intrinsically higher in nodes of Ranvier even in resting conditions. Axonal firing increased both ATP and H 2 O 2 productions but with different dynamics: ROS production peaked shortly and transiently after the stimulation while ATP production increased gradually for a longer period of time. In neuropathic MFN2 R94Q mice, mimicking Charcot-Marie-Tooth 2A disease, defective mitochondria failed to upregulate ATP production following axonal activity. However, elevated H 2 O 2 production was largely sustained. Finally, inducing demyelination with lysophosphatidylcholine resulted in a reduced level of ATP while H 2 O 2 level soared. Taken together, our results suggest that ATP and ROS productions are decoupled under neuropathic conditions, which may compromise axonal function and integrity. Electronic supplementary material The online version of this article (10.1186/s40478-019-0740-4) contains supplementary material, which is available to authorized users.