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Lactate from astrocytes fuels learning-induced mRNA translation in excitatory and inhibitory neurons

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Descalzi, Giannina, Gao, Virginia, Steinman, Michael Q., Suzuki, Akinobu, Alberini, Cristina M.·2019·Communications Biology
DOI 10.1038/s42003-019-0495-2PMC PMC6606643
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Abstract

Glycogenolysis and lactate transport from astrocytes to neurons is required for long-term memory formation, but the role of this lactate is poorly understood. Here we show that the Krebs cycle substrates pyruvate and ketone body B3HB can functionally replace lactate in rescuing memory impairment caused by inhibition of glycogenolysis or expression knockdown of glia monocarboxylate transporters (MCTs) 1 and 4 in the dorsal hippocampus of rats. In contrast, either metabolite is unable to rescue memory impairment produced by expression knockdown of MCT2, which is selectively expressed by neurons, indicating that a critical role of astrocytic lactate is to provide energy for neuronal responses required for long-term memory. These responses include learning-induced mRNA translation in both excitatory and inhibitory neurons, as well as expression of Arc/Arg3.1. Thus, astrocytic lactate acts as an energy substrate to fuel learning-induced de novo neuronal translation critical for long-term memory.

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Fig. 1 Memory impairments caused by blockade of glycogenolysis are rescued by pyruvate or B3HB. Memory retention expressed as mean latency ± SEM (in seconds, s). Timeline is presented above graphs. a A bilateral intra-dHP injection of vehicle (Veh), DAB (300 pmol), or DAB + pyruvate (Pyr) (100 nmol), was given 15 min before IA training (black arrow), and IA memory retention was tested 2 (T1) and 7 days (T2) after training. n = 9/group, two-way RM ANOVA, SNK; 4 independent experiments. b A bilateral intra-dHP injection of vehicle (Veh) or pyruvate (Pyr) was given 15 min before IA training (black arrow), and IA memory retention was tested 2 (T1) and 7 days (T2) after training. n = 6/group, two-way RM ANOVA; 3 independent experiments. c A bilateral intra-dHP injection of vehicle (Veh, n = 10), DAB (300 pmol, n = 10), DAB + B3HB (72 nmol, n = 10), or B3HB (n = 9) alone was given 15 min before IA training, and IA memory retention was tested 2 (T1) and 7 days (T2) after training. Two-way RM ANOVA, SNK; 6 independent experiments. d A bilateral intra-dHP injection of vehicle (Veh, n = 5), DAB (n = 6), or DAB + glucose (Gluc, 50 nmol, n = 6), was given 15 min before IA training (black arrow), and IA memory retention was tested 2 (T1) and 7 days (T2) after training. Two-way RM ANOVA, SNK. 3 independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for detailed statistical information
Fig. 1 Memory impairments caused by blockade of glycogenolysis are rescued by pyruvate or B3HB. Memory retention expressed as mean latency ± SEM (in seconds, s). Timeline is presented above graphs. a A bilateral intra-dHP injection of vehicle (Veh), DAB (300 pmol), or DAB + pyruvate (Pyr) (100 nmol), was given 15 min before IA training (black arrow), and IA memory retention was tested 2 (T1) and 7 days (T2) after training. n = 9/group, two-way RM ANOVA, SNK; 4 independent experiments. b A bilateral intra-dHP injection of vehicle (Veh) or pyruvate (Pyr) was given 15 min before IA training (black arrow), and IA memory retention was tested 2 (T1) and 7 days (T2) after training. n = 6/group, two-way RM ANOVA; 3 independent experiments. c A bilateral intra-dHP injection of vehicle (Veh, n = 10), DAB (300 pmol, n = 10), DAB + B3HB (72 nmol, n = 10), or B3HB (n = 9) alone was given 15 min before IA training, and IA memory retention was tested 2 (T1) and 7 days (T2) after training. Two-way RM ANOVA, SNK; 6 independent experiments. d A bilateral intra-dHP injection of vehicle (Veh, n = 5), DAB (n = 6), or DAB + glucose (Gluc, 50 nmol, n = 6), was given 15 min before IA training (black arrow), and IA memory retention was tested 2 (T1) and 7 days (T2) after training. Two-way RM ANOVA, SNK. 3 independent experiments. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 1 for detailed statistical informationCC BY · PubMed Central
Fig. 2 Memory impairments caused by expression knockdown of MCT1 and MCT4, but not of MCT2, are rescued by pyruvate or B3HB. Memory retention expressed as mean latency ± SEM (in seconds, s). Timeline is presented above graphs. Rats received a bilateral intra-dHP injection of related scrambled (SCR) oligodeoxynucleotide (ODNs) sequences, or antisense (AS) ODNs against MCT1 (a, n = 8), MCT4 (b, n = 11), or MCT1 + MCT4 (c, n = 12), 1 h before training (red arrow), and (a–c) vehicle (Veh, a: n = 8, b and c: n = 12) or pyruvate (Pyr; 100 nmol, a: n = 8, b and c: n = 12) 15 min before training (black arrow). Two-way RM ANOVA, SNK; 4 independent experiments. d Memory tested 2 days (T1) and 7 d (T2) after training in animals that received bilateral dHP injection of MCT1 + 4 SCR-ODNs (SCR) 1 h before training (red arrow), and bilateral injection of vehicle, B3HB, or pyruvate (Pyr), 15 min before training (black arrow). n = 6 rats/group, two-way RM ANOVA; 3 independent experiments. e Memory tested 2 days (T1) and 7 d (T2) after training in animals that received bilateral dHP injection of MCT2-SCR-ODNs (SCR) or MCT2-AS ODNs 1 h before training (red arrow) and bilateral injection of vehicle (Veh, n = 12), pyruvate (Pyr; SCR: n = 10, AS: n = 12), or B3HB (n = 10) 15 min before training (black arrow). Six independent experiments; Two-way RM ANOVA, SNK. **p < 0.01, ***p < 0.001. See Supplementary Table 2 for detailed statistical information
Fig. 2 Memory impairments caused by expression knockdown of MCT1 and MCT4, but not of MCT2, are rescued by pyruvate or B3HB. Memory retention expressed as mean latency ± SEM (in seconds, s). Timeline is presented above graphs. Rats received a bilateral intra-dHP injection of related scrambled (SCR) oligodeoxynucleotide (ODNs) sequences, or antisense (AS) ODNs against MCT1 (a, n = 8), MCT4 (b, n = 11), or MCT1 + MCT4 (c, n = 12), 1 h before training (red arrow), and (a–c) vehicle (Veh, a: n = 8, b and c: n = 12) or pyruvate (Pyr; 100 nmol, a: n = 8, b and c: n = 12) 15 min before training (black arrow). Two-way RM ANOVA, SNK; 4 independent experiments. d Memory tested 2 days (T1) and 7 d (T2) after training in animals that received bilateral dHP injection of MCT1 + 4 SCR-ODNs (SCR) 1 h before training (red arrow), and bilateral injection of vehicle, B3HB, or pyruvate (Pyr), 15 min before training (black arrow). n = 6 rats/group, two-way RM ANOVA; 3 independent experiments. e Memory tested 2 days (T1) and 7 d (T2) after training in animals that received bilateral dHP injection of MCT2-SCR-ODNs (SCR) or MCT2-AS ODNs 1 h before training (red arrow) and bilateral injection of vehicle (Veh, n = 12), pyruvate (Pyr; SCR: n = 10, AS: n = 12), or B3HB (n = 10) 15 min before training (black arrow). Six independent experiments; Two-way RM ANOVA, SNK. **p < 0.01, ***p < 0.001. See Supplementary Table 2 for detailed statistical informationCC BY · PubMed Central
Fig. 3 Lactate or pyruvate support learning-induced mRNA translation in both inhibitory and excitatory neurons. Data are expressed as mean % ± SEM of untrained controls (100%). SUnSET in the dHP of untrained and trained rats and its dependence on glycogenolysis and lactate. a Puromycin was co-injected with vehicle (Veh, naive, n = 12, trained n = 9), DAB (300pmol, n = 11), DAB + L-lactate (at 100 nmol, n = 9), or pyruvate (Pyr at 100 nmol, n = 10) 15 min before training. Two hours after training, dHP protein extracts were assessed for puromycin labeling via western blotting; β-tubulin was used as loading control. A control sample not injected with Puro (Ctrl) was included. Four independent experiments. See Supplementary Figure 1 for a representative SUnSET full western blot. One-way ANOVA, Tukey. b–g A dHP bilateral injection of puromycin with vehicle (Veh), DAB, DAB + L-lactate (DAB + Lac), or DAB + pyruvate (DAB + Pyr) 15 min before training. Rats were perfused 2 h after training. Brain slices were co-immunostained for puromycin (Puro) and b CaMKIIα or c parvalbumin (PV); Three independent experiments. b, c representative immunostaining examples and d, e relative quantifications expressed in mean % ± SEM of untrained controls (100%) of CaMKIIα in d the dHP CA1 (Untrained: n = 21, Veh: n = 25, DAB: n = 20, DAB + Lac: n = 27) and e dHP DG (Untrained: n = 21, Veh: 27, DAB: 23, DAB + Lac: n = 27); Three independent experiments. f, g Relative quantifications expressed in mean % ± SEM of untrained controls (100%) of PV + cells in f dHP CA1 (Untrained: n = 21, Veh: n = 25, DAB: n = 20, DAB + Lac: n = 27) and g dHP DG (Untrained: n = 33, Veh: n = 45, DAB: n = 45, DAB + Lac: n = 38); Three independent experiments. One-way ANOVA, Tukey. *p < 0.05, **p < 0.01, ***p < 0.001. Scale bars = 50 µM; see Supplementary Table 3 for detailed statistical information
Fig. 3 Lactate or pyruvate support learning-induced mRNA translation in both inhibitory and excitatory neurons. Data are expressed as mean % ± SEM of untrained controls (100%). SUnSET in the dHP of untrained and trained rats and its dependence on glycogenolysis and lactate. a Puromycin was co-injected with vehicle (Veh, naive, n = 12, trained n = 9), DAB (300pmol, n = 11), DAB + L-lactate (at 100 nmol, n = 9), or pyruvate (Pyr at 100 nmol, n = 10) 15 min before training. Two hours after training, dHP protein extracts were assessed for puromycin labeling via western blotting; β-tubulin was used as loading control. A control sample not injected with Puro (Ctrl) was included. Four independent experiments. See Supplementary Figure 1 for a representative SUnSET full western blot. One-way ANOVA, Tukey. b–g A dHP bilateral injection of puromycin with vehicle (Veh), DAB, DAB + L-lactate (DAB + Lac), or DAB + pyruvate (DAB + Pyr) 15 min before training. Rats were perfused 2 h after training. Brain slices were co-immunostained for puromycin (Puro) and b CaMKIIα or c parvalbumin (PV); Three independent experiments. b, c representative immunostaining examples and d, e relative quantifications expressed in mean % ± SEM of untrained controls (100%) of CaMKIIα in d the dHP CA1 (Untrained: n = 21, Veh: n = 25, DAB: n = 20, DAB + Lac: n = 27) and e dHP DG (Untrained: n = 21, Veh: 27, DAB: 23, DAB + Lac: n = 27); Three independent experiments. f, g Relative quantifications expressed in mean % ± SEM of untrained controls (100%) of PV + cells in f dHP CA1 (Untrained: n = 21, Veh: n = 25, DAB: n = 20, DAB + Lac: n = 27) and g dHP DG (Untrained: n = 33, Veh: n = 45, DAB: n = 45, DAB + Lac: n = 38); Three independent experiments. One-way ANOVA, Tukey. *p < 0.05, **p < 0.01, ***p < 0.001. Scale bars = 50 µM; see Supplementary Table 3 for detailed statistical informationCC BY · PubMed Central
Fig. 4 Lactate or pyruvate rescues the disruption of Arc/Arg3.1 expression caused by DAB. Representative examples a and relative quantifications b of Arc/Arg3.1 immunostaining in the dHC of untrained and trained rats injected as described. Data are expressed as mean % ± SEM of untrained controls (100%). A bilateral dHP injection of vehicle (Veh), DAB (300 pmol), DAB + L-lactate (Lac, 100 nmol), or DAB + pyruvate (Pyr, 100 nmol) was given 15 min before training, and the rats were perfused 1 h after training and compared to untrained rats injected with Veh. a Fluorescent images of Arc/Arg3.1 immunostaining in the dorsal hippocampus (left, scale bar = 500 µM), and higher magnifications (confocal images) of CA1 (middle, scale bar = 50 µM), and DG (right, scale bar = 50 µM). b Relative quantification of Arc/Arg3.1 immunohistochemical staining in CA1 (n = 3 rats /group; 3 brain slices per rat); 3 independent experiments. c Relative quantification of Arc/Arg3.1 immunohistochemical staining in DG (Untrained: n = 3, Veh: n = 3, DAB: n = 4, DAB + Lac: n = 4, DAB + Pyr: n = 3; 3 brain slices per rat); 3 independent experiments. One-way ANOVA, Tukey. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 4 for detailed statistical information
Fig. 4 Lactate or pyruvate rescues the disruption of Arc/Arg3.1 expression caused by DAB. Representative examples a and relative quantifications b of Arc/Arg3.1 immunostaining in the dHC of untrained and trained rats injected as described. Data are expressed as mean % ± SEM of untrained controls (100%). A bilateral dHP injection of vehicle (Veh), DAB (300 pmol), DAB + L-lactate (Lac, 100 nmol), or DAB + pyruvate (Pyr, 100 nmol) was given 15 min before training, and the rats were perfused 1 h after training and compared to untrained rats injected with Veh. a Fluorescent images of Arc/Arg3.1 immunostaining in the dorsal hippocampus (left, scale bar = 500 µM), and higher magnifications (confocal images) of CA1 (middle, scale bar = 50 µM), and DG (right, scale bar = 50 µM). b Relative quantification of Arc/Arg3.1 immunohistochemical staining in CA1 (n = 3 rats /group; 3 brain slices per rat); 3 independent experiments. c Relative quantification of Arc/Arg3.1 immunohistochemical staining in DG (Untrained: n = 3, Veh: n = 3, DAB: n = 4, DAB + Lac: n = 4, DAB + Pyr: n = 3; 3 brain slices per rat); 3 independent experiments. One-way ANOVA, Tukey. *p < 0.05, **p < 0.01, ***p < 0.001. See Supplementary Table 4 for detailed statistical informationCC BY · PubMed Central

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Research works printed but not linked: 1

  1. Okada, Y. & Lipton, P. in Handbook of Neurochemistry and Molecular Neurobiology: Brain Energetics. Integration of Molecular and Cellular Processes (eds Abel Lajtha, Gary E. Gibson, & Gerald A. Dienel) 17–39 (Springer US, 2007).

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Metadata

Authors
Descalzi, G., Gao, V., Steinman, M. Q., Suzuki, A., & Alberini, C. M.
Affiliations
  • New York University (US)
  • University of Toyama (JP)
Corresponding author
Alberini, Cristina M.
ORCID
Venue
Communications Biology
Publisher
Springer Science and Business Media LLC
Published
2019-07-02
Volume
2
Issue
1
Pages
247-247
ISSN
2399-3642 (ISSN-L)
DOI
10.1038/s42003-019-0495-2
PMC
PMC6606643
OpenAlex
W2954464051
Cited by
188
References
69
Citations by year
2026: 29 · 2025: 31 · 2024: 31 · 2023: 24 · 2022: 27 · 2021: 27 · 2020: 19
FWCI
10.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Communications Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (MH100822)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
astrocyte-neuron lactate shuttle, long-term memory, pyruvate, ketone bodies, glycogenolysis, monocarboxylate transporters, MCT1, MCT2, MCT4, hippocampus, Arc/Arg3.1, neuronal energy metabolism, excitatory neurons, inhibitory neurons
MeSH terms
Memory Consolidation, Animals, Astrocytes, Avoidance Learning, Brain, Citric Acid Cycle, Gangliosides, Hippocampus, Male, Memory Disorders, Neurons, RNA, Messenger, Pyruvic Acid, Lactic Acid, Rats, Long-Evans, Monocarboxylic Acid Transporters, Glycogenolysis, Rats, Memory, Episodic

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