Lactate ions induce synaptic plasticity to enhance output from the central respiratory network

Abstract

Lactate ion sensing has emerged as a process that regulates ventilation during metabolic challenges. Most work has focused on peripheral sensing of lactate for the control of breathing. However, lactate also rises in the central nervous system (CNS) during disturbances to blood gas homeostasis and exercise. Using an amphibian model, we recently showed that lactate ions, independently of pH and pyruvate metabolism, act directly in the brainstem to increase respiratory‐related motor outflow. This response had a long washout time and corresponded with potentiated excitatory synaptic strength of respiratory motoneurons. Thus, we tested the hypothesis that lactate ions enhance respiratory output using cellular mechanisms associated with long‐term synaptic plasticity within motoneurons. In this study, we confirm that 2 mM sodium lactate, but not sodium pyruvate, increases respiratory motor output in brainstem‐spinal cord preparations, persisting for 2 h upon the removal of lactate. Lactate also led to prolonged increases in the amplitude of AMPA‐glutamate receptor (AMPAR) currents in individual motoneurons from brainstem slices. Both motor facilitation and AMPAR potentiation by lactate required classic effectors of synaptic plasticity, L‐type Ca2+ channels and NMDA receptors, as part of the transduction process but did not correspond with increased expression of immediate‐early genes often associated with activity‐dependent neuronal plasticity. Altogether these results show that lactate ions enhance respiratory motor output by inducing conserved mechanisms of synaptic plasticity and suggest a new mechanism that may contribute to coupling ventilation to metabolic demands in vertebrates. Key points Lactate ions, independently of pH and metabolism, induce long‐term increases in respiratory‐related motor outflow in American bullfrogs. Lactate triggers a persistent increase in strength of AMPA‐glutamatergic synapses onto respiratory motor neurons. Long‐term plasticity of motor output and synaptic strength by lactate involves L‐type Ca2+ channels and NMDA‐receptors as part of the transduction process. Enhanced AMPA receptor function in response to lactate in the intact network is causal for motor plasticity. In sum, well‐conserved synaptic plasticity mechanisms couple the brainstem lactate ion concentration to respiratory motor drive in vertebrates.

Inactivity and Ca2+ signaling regulate synaptic compensation in motoneurons following hibernation in American bullfrogs

“…To upregulate synaptic strength in an inactivity-dependent manner, we hypothesized that reduced Ca 2+ influx through voltage-gated Ca 2+ channels may play a role. Thus, we exposed rhythmic circuit preparations to 10 μM nimodipine, a blocker of L-type Ca 2+ channels in motoneurons of this system 30 for 16 hrs. Exposure of warm-acclimated preparations to nimodipine did not affect mean mEPSC amplitude or the distribution relative to warm-acclimated time controls (Fig.…”

“…Although our data rule out the possibly for a role by nimodipine-sensitive L-type Ca 2+ channels in compensation, other Ca 2+ channels may contribute. For example, in respiratory motor neurons of this species, nimodipine blocks the high-voltage activated Ca 2+ current by ~30-40% 30 , indicating the expression of other somatodendritic calcium channels on respiratory motoneurons. Nevertheless, L-type Ca 2+ channels do not appear to drive synaptic compensation, differing from traditional models in neuronal cultures 22,25,26,38 .…”

“…TTX silenced all preparations for the entire 16 hr period (data not shown). In series three experiments, we exposed warm-acclimated control and posthibernation rhythmic preparations to 10 μM nimodipine for 16 hrs to block L-type Ca 2+ channels, a dose that blocks these channels in frog respiratory motoneurons 30 , and a separate time control group was run in parallel. Following these treatments all mEPSC recordings were performed in standard aCSF with 500 nM TTX.…”

Plasticity in the functional properties of NMDA receptors improves network stability during severe energy stress

“…Although our results show strong support for NMDAR plasticity as a potential energy-saving mechanism, they also hint at a potential cost of maintaining an “ultra-high” efficiency network state. NMDARs play a key role in plasticity, whereby Ca 2+ influx through the receptor potentiates synaptic strength in a wide range of systems, including the respiratory motoneurons in this species (Bueschke et al, 2021b). NMDAR modifications we observe likely incur an energy savings but have features that appear to be incompatible with NMDAR-dependent plasticity: strongly reduced Ca 2+ permeability and greatly enhanced desensitization which quickly reduces channel activity upon repetitive stimulation.…”

Perception is associated with the brain’s metabolic response to sensory stimulation

“…Elevated brain lactate and glutamate levels are associated with wakefulness and memory formation, which naturally require the processing of incoming sensory stimuli, like the control exerted by the central visual pathways for either gating or filtering out behaviorally relevant or irrelevant visual information. As such, the metabolic responses to perceived, but not unperceived, sensory stimulation could be enabling factors for learning and memory, as indicated by the relevance of aerobic glycolysis and lactate in synaptic plasticity mechanisms ( Bueschke et al, 2021 ; Descalzi et al, 2019 ; DiNuzzo, 2016 ; Harris et al, 2019 ; Herrera-López et al, 2020 ; Jourdain et al, 2018 ; Kobayashi et al, 2019 ; Lundquist et al, 2021 ; Margineanu et al, 2018 ; Scavuzzo et al, 2020 ; Wang et al, 2019 ; Yang et al, 2014 ). In particular, aerobic glycolysis and lactate might reflect cortical information processing and, in turn, intracortical communication, in agreement with the relation between regional metabolic rates of glucose utilization and resting-state network dynamics in the cerebral cortex ( Jamadar et al, 2020 ; Noack et al, 2017 ; Spetsieris et al, 2015 ; Su et al, 2018 ; Thompson, 2018 ).…”