Lactate Attenuates Synaptic Transmission and Affects Brain Rhythms Featuring High Energy Expenditure

Hollnagel, Jan‐Oliver; Cesetti, Tiziana; Schneider, Justus; Vazetdinova, Alina; Valiullina-Rakhmatullina, Fliza; Lewen, Andrea; Rozov, Andrei; Kann, Oliver

doi:10.1016/j.isci.2020.101316

Cited by 38 publications

(79 citation statements)

References 119 publications

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“…Moreover, increased D-glucose utilization may result in excessive local L-lactate availability for J o u r n a l P r e -p r o o f synapses. Recent data reported that lactate attenuates glutamatergic synaptic transmission and perturbs network oscillations in gamma and theta-gamma frequency ranges in hippocampal slices [55], again supporting the view that synaptic and cognitive deficits in our model are caused by metabolic dysfunctions.…”

Section: J O U R N a L P R E -P R O O Fsupporting

confidence: 87%

Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse

et al. 2021

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Objectives GDI1 gene encodes for αGDI, a protein controlling the cycling of small GTPases, reputed to orchestrate vesicle trafficking. Mutations in human GDI1 are responsible for intellectual disability (ID). In mice with ablated Gdi1 , a model of ID, impaired working and associative short-term memory was recorded. This cognitive phenotype worsens if the deletion of αGDI expression is restricted to neurons. However, whether astrocytes, key homeostasis providing neuroglial cells, supporting neurons via aerobic glycolysis, contribute to this cognitive impairment is unclear. Methods We carried out proteomic analysis and monitored [ 18 F]-fluoro-2-deoxy- d -glucose uptake into brain slices of Gdi1 knockout and wild type control mice. d -Glucose utilization at single astrocyte level was measured by the Förster Resonance Energy Transfer (FRET)-based measurements of cytosolic cyclic AMP, d -glucose and L-lactate, evoked by agonists selective for noradrenaline and L-lactate receptors. To test the role of astrocyte-resident processes in disease phenotype, we generated an inducible Gdi1 knockout mouse carrying the Gdi1 deletion only in adult astrocytes and conducted behavioural tests. Results Proteomic analysis revealed significant changes in astrocyte-resident glycolytic enzymes. Imaging [ 18 F]-fluoro-2-deoxy- d -glucose revealed an increased d -glucose uptake in Gdi1 knockout tissue versus wild type control mice, consistent with the facilitated d -glucose uptake determined by FRET measurements. In mice with Gdi1 deletion restricted to astrocytes, a selective and significant impairment in working memory was recorded, which was rescued by inhibiting glycolysis by 2-deoxy- d -glucose injection. Conclusions These results reveal a new astrocyte-based mechanism in neurodevelopmental disorders and open a novel therapeutic opportunity of targeting aerobic glycolysis, advocating a change in clinical practice.

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Section: J O U R N a L P R E -P R O O Fsupporting

confidence: 87%

Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse

et al. 2021

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“…Indeed, ex-vivo slice studies directly linked lactate-concentration to the disruption the neuronal excitation-inhibition balance, speci cally by reducing gamma-band rhythm due to transient ATP-shortage in fast-spiking inhibitory interneurons 36 . Interestingly, sharp wave-ripples, lower-energy expenditure oscillations characterizing waking immobility and slow-wave sleep, were not perturbed by lactate injection 37 .…”

Section: Discussionmentioning

confidence: 94%

Frontal increase of movement-related beta modulation is enhanced by visuo-motor learning

Tatti¹,

Ferraioli²,

Peter³

et al. 2021

Preprint

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Recently we found that enhancements of movement-related beta (13.5–25 Hz) modulation (measured as event-related desynchronization peak to synchronization peak) during a simple reaching test (mov) occur over frontal and left sensorimotor regions after extended practice in a visuo-motor adaptation task (ROT) but not after similar duration practice in a visual learning task. Here we verify whether those enhancements are also trigged by motor practice alone or the additional learning component inherent in the visuo-motor adaptation task is needed. In healthy young subjects, beta modulation during mov increased over frontal and contralateral sensorimotor areas after three-hour practice of either ROT or reaching movements without visuo-motor adaptation (MOT). However, while the increase over the left area was similar after the two tasks, the frontal increase was greater after ROT practice. These findings confirm previous reports that extensive practice leaves local traces in beta power both at rest and during the subsequent execution of a motor test. They further suggest that, since they occur after motor tasks with (ROT) and without learning (MOT), these traces likely express the cost of processes necessary both for usage of these areas and for the engagement of long-term potentiation mechanisms necessary for creating new internal models.

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“…Finally, lactate may have a neuroprotective effect through reducing excitotoxicity. Indeed, it was recently shown on hippocampal slices that lactate in the medium can reduce neurotransmitter content at both excitatory and inhibitory synapses, thus limiting excitotoxicity, which is present during hypoxia-ischemia ( Hollnagel et al, 2020 ). To conclude, we can hypothesize that resveratrol, in addition to its antioxidant, anti-apoptotic and anti-inflammatory properties, may also be neuroprotective by targeting key partners of the ANLS.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Maternal Resveratrol Supplementation in a Rat Model of Neonatal Hypoxia-Ischemia

et al. 2021

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Neonatal hypoxia-ischemia (nHI) is a major cause of death or subsequent disabilities in infants. Hypoxia-ischemia causes brain lesions, which are induced by a strong reduction in oxygen and nutrient supply. Hypothermia is the only validated beneficial intervention, but not all newborns respond to it and today no pharmacological treatment exists. Among possible therapeutic agents to test, trans-resveratrol is an interesting candidate as it has been reported to exhibit neuroprotective effects in some neurodegenerative diseases. This experimental study aimed to investigate a possible neuroprotection by resveratrol in rat nHI, when administered to the pregnant rat female, at a nutritional dose. Several groups of pregnant female rats were studied in which resveratrol was added to drinking water either during the last week of pregnancy, the first week of lactation, or both. Then, 7-day old pups underwent a hypoxic-ischemic event. Pups were followed longitudinally, using both MRI and behavioral testing. Finally, a last group was studied in which breastfeeding females were supplemented 1 week with resveratrol just after the hypoxic-ischemic event of the pups (to test the curative rather than the preventive effect). To decipher the molecular mechanisms of this neuroprotection, RT-qPCR and Western blots were also performed on pup brain samples. Data clearly indicated that when pregnant and/or breastfeeding females were supplemented with resveratrol, hypoxic-ischemic offspring brain lesions were significantly reduced. Moreover, maternal resveratrol supplementation allowed to reverse sensorimotor and cognitive deficits caused by the insult. The best recoveries were observed when resveratrol was administered during both gestation and lactation (2 weeks before the hypoxic-ischemic event in pups). Furthermore, neuroprotection was also observed in the curative group, but only at the latest stages examined. Our hypothesis is that resveratrol, in addition to the well-known neuroprotective benefits via the sirtuin’s pathway (antioxidant properties, inhibition of apoptosis), has an impact on brain metabolism, and more specifically on the astrocyte-neuron lactate shuttle (ANLS) as suggested by RT-qPCR and Western blot data, that contributes to the neuroprotective effects.

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Lactate Attenuates Synaptic Transmission and Affects Brain Rhythms Featuring High Energy Expenditure

Cited by 38 publications

References 119 publications

Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse

Inhibiting glycolysis rescues memory impairment in an intellectual disability Gdi1-null mouse

Frontal increase of movement-related beta modulation is enhanced by visuo-motor learning

Neuroprotective Effect of Maternal Resveratrol Supplementation in a Rat Model of Neonatal Hypoxia-Ischemia

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