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Review
. 2018 Jun;66(6):1244-1262.
doi: 10.1002/glia.23250. Epub 2017 Oct 27.

Astrocyte glycogen and lactate: New insights into learning and memory mechanisms

Affiliations
Review

Astrocyte glycogen and lactate: New insights into learning and memory mechanisms

Cristina M Alberini et al. Glia. 2018 Jun.

Abstract

Memory, the ability to retain learned information, is necessary for survival. Thus far, molecular and cellular investigations of memory formation and storage have mainly focused on neuronal mechanisms. In addition to neurons, however, the brain comprises other types of cells and systems, including glia and vasculature. Accordingly, recent experimental work has begun to ask questions about the roles of non-neuronal cells in memory formation. These studies provide evidence that all types of glial cells (astrocytes, oligodendrocytes, and microglia) make important contributions to the processing of encoded information and storing memories. In this review, we summarize and discuss recent findings on the critical role of astrocytes as providers of energy for the long-lasting neuronal changes that are necessary for long-term memory formation. We focus on three main findings: first, the role of glucose metabolism and the learning- and activity-dependent metabolic coupling between astrocytes and neurons in the service of long-term memory formation; second, the role of astrocytic glucose metabolism in arousal, a state that contributes to the formation of very long-lasting and detailed memories; and finally, in light of the high energy demands of the brain during early development, we will discuss the possible role of astrocytic and neuronal glucose metabolisms in the formation of early-life memories. We conclude by proposing future directions and discussing the implications of these findings for brain health and disease. Astrocyte glycogenolysis and lactate play a critical role in memory formation. Emotionally salient experiences form strong memories by recruiting astrocytic β2 adrenergic receptors and astrocyte-generated lactate. Glycogenolysis and astrocyte-neuron metabolic coupling may also play critical roles in memory formation during development, when the energy requirements of brain metabolism are at their peak.

Keywords: development; emotional arousal; glia; glucose; glycogenolysis; glycolysis; metabolism.

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Conflict of interest statement

The authors declare they have no conflicts of interest

Figures

Figure 1
Figure 1. Schematic example of neuron-centric molecular pathways underlying long-term memory formation
Most literature’s figures available thus far illustrating molecular mechanisms underlying learning and memory depict only pre and postsynaptic neurons and relative mechanisms of interest. One example is the following: learning-induced release of neurotransmitters (e.g. glutamate) and of neuronal growth factors (e.g. BDNF) activate different families of receptors, enabling the recruitment of various intracellular signaling pathways involving second messengers (e.g. Ca2+, cAMP) and protein kinases (e.g. CamKII, PKA). These signaling pathways regulate: 1) post-translational modifications [e.g., phosphorylation (P) of postsynaptic glutamatergic receptors]; 2) activation of a CREB-regulated gene cascade leading to the expression of target genes, including IEGs (e.g., C/EBP, c-Fos, Zif268), which in turn regulate the expression of late response genes critical for long-lasting functional (e.g., membrane translocation of new receptors) and structural neuronal changes (e.g., dendritic spine morphological changes). This gene expression is regulated by epigenetic mechanisms [e.g. histone acetylation and/or methylation (M), DNA methylation] as well as by several post-transcriptional and translational mechanisms including the mTOR pathway and microRNAs. Abbreviations: AC (adenylyl cyclase); AKT (protein kinase B or Akt); AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor); BDNF (brain-derived neurotrophic factor); CaM (calmodulin); CaMKII/IV (Ca++-calmodulin kinase II/IV); cAMP (cyclic adenosine monophosphate); C/EBP (CCAAT/enhancer binding protein); CRE (cAMP response element); CREB (cAMP response element binding protein); DAG (diacylglycerol); GPCR (G protein–coupled receptors); IEGs (immediate early genes); IP3 (inositol trisphosphate); IP3R (inositol trisphosphate receptor); MSK (mitogen and stress activated protein kinase); mTOR (mammalian target of rapamycin); NMDAR (N-methyl-D-aspartate receptor); p70S6K (ribosomal protein S6 kinase beta-1); PI3K (phosphoinositide 3-kinase); PKA (protein kinase A); PKC (protein kinase C); PKMζ(protein kinase M zeta); PLC (phospholipase C); PSD-95 (post-synaptic density 95); RSK (ribosomal s6 kinase family); Src (proto-oncogene tyrosine-protein kinase); TGs (target genes); Trk (tyrosine receptor kinase); VSCC (voltage-sensitive calcium channel). Notably, multiple cell types in the brain express many of these mechanisms.
Figure 2
Figure 2. Astrocyte–neuron lactate coupling in long-term memory formation
Glucose is taken up by astrocytes from surrounding capillaries via glucose transporters (GLUT1). Glucose can then be stored as glycogen in astrocytes or undergo glycolysis to become pyruvate. In astrocytes, pyruvate can be transported into the mitochondria or converted to lactate, which can be exported out of the astrocyte by the monocarboxylate transporter 1 or 4 (MCT1/4) and transported into neurons via MCT2. In neurons, astrocytic-derived lactate is converted back into pyruvate and transported into the mitochondria to generate ATP. Glucose may also be transported from the capillaries into neurons through the glucose transporter (GLUT3). In Suzuki et al. 2011, we showed that the astrocytic-derived lactate from glycogenolysis is critical for long-term memory formation in rats and for the underlying regulation of molecular changes required for long-term memory formation. These changes include the phosphorylation of the transcription factor CREB, the expression of target genes (TGs), the expression of immediate early genes such as Arc, and the phosphorylation of the actin-binding protein cofilin. Whether glucose transport into neurons through GLUT3 is important for memory formation remains to be determined.
Figure 3
Figure 3. Blocking glycogenolysis in the basolateral amygdala impairs long-term memory
Long-term memory retention, expressed as mean latency values ± SEM in seconds (s), tested 1 day (d) after training (Test 1), 6 d later (Test 2), and after a reminder shock given in a distinct context (RS, Test 3). Vehicle, DAB (300 pmol), or DAB (300 pmol) + L-lactate (100 nmol) was injected bilaterally into the basolateral amygdala (BLA) 15 min prior to inhibitory avoidance (IA) training (red arrow). Statistical significance was assessed by two-way ANOVA followed by Bonferroni’s post hoc tests compared to vehicle (**p < 0.01; ***p < 0.001; n = 7–8/group).

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