Synaptic activity‐induced glycolysis facilitates membrane lipid provision and neurite outgrowth

Segarra‐Mondejar, Marc; Casellas‐Díaz, Sergi; Ramiro-Pareta, Marina; Müller‐Sánchez, Claudia; Martorell‐Riera, Alejandro; Hermelo, Ismaïl; Reina, Manuel; Aragonés, Julián; Martínez-Estrada, Ofelia M.; Soriano, Francesc X.

doi:10.15252/embj.201797368

Cited by 41 publications

(47 citation statements)

References 91 publications

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“…2) [58]. Biosynthesis of macromolecules from glucose metabolites is critical to support key physiological processes behind proper brain growth and maturation; it has been shown, for example, that axon growth, synapse formation, and myelination rely critically on aerobic glycolysis [20,59,60]. Interestingly, aerobic glycolysis is predominant in the white matter compared to the gray matter, and it has been shown that glycolytic byproducts, such as lactate, are especially important for myelin production by oligodendrocytes [61,62].…”

Section: Glucose Requirements To Support Energy and Anabolic Demands mentioning

confidence: 99%

Brain Fuel Utilization in the Developing Brain

Steiner

2019

Ann Nutr Metab

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During pregnancy and infancy, the human brain is growing extremely fast; the brain volume increases significantly, reaching 36, 72, and 83% of the volume of adults at 2–4 weeks, 1 year, and 2 years of age, respectively, which is essential to establish the neuronal networks and capacity for the development of cognitive, motor, social, and emotional skills that will be continually refined throughout childhood and adulthood. Such dramatic changes in brain structure and function are associated with very large energetic demands exceeding by far those of other organs of the body. It has been estimated that during childhood the brain may account for up to 60% of the body basal energetic requirements. While the main source of energy for the adult brain is glucose, it appears that it is not sufficient to sustain the dramatic metabolic demands of the brain during its development. Recently, it has been proposed that this energetic challenge is solved by the ability of the brain to use ketone bodies (KBs), produced from fatty acid oxidation, as a complement source of energy. Here, we first describe the main cellular and physiological processes that drive brain development along time and how different brain metabolic pathways are engaged to support them. It has been assumed that the majority of energetic substrates are used to support neuronal activity and signal transmission. We discuss how glucose and KBs are metabolized to provide the carbon backbones used to synthesize lipids, nucleic acid, and cholesterol, which are indispensable building blocks of neuronal cell proliferation and are also used to establish and refine brain connectivity through synapse formation/elimination and myelination. We conclude that glucose and KBs are not only important to support the energy needs of the brain under development, but they are also essential substrates for the biosynthesis of macromolecules underlying structural brain growth and reorganization. We emphasize that glucose and fatty acids supporting the production of KBs are provided in complex food matrices, such as breast milk, and understanding how their availability impacts the brain will be key to promote adequate nutrition to support brain metabolism and, therefore, optimal brain development.

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Section: Glucose Requirements To Support Energy and Anabolic Demands mentioning

confidence: 99%

Brain Fuel Utilization in the Developing Brain

Steiner

2019

Ann Nutr Metab

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“…The protocol was as previously reported with slight modifications. 31,32 Briefly, E17-18 fetuses from the same pregnant Sprague-Dawley rat were used for primary cultures of cortical neurons. Brains were carefully dissected with fine scissors, and cortices were isolated and the meninges were removed with fine forceps in ice-cold DMEM.…”

Section: Primary Rat Cortical Neuron Culturementioning

confidence: 99%

“…Previous studies have reported that GLUT3 is translated by transcriptional factor CREB and Hif-1α. 31,52 Hif-1α is quickly degraded under normoxic conditions and is nearly undetectable. 31 Therefore, CREB protein which also F I G U R E 4 Upregulating GLUT3 increases mPFC glucose uptake and ameliorates depressive-like behaviors of PSD rats.…”

Section: Pka/pcreb Signaling Pathway In Ogd/r Treated Primary Neuronsmentioning

confidence: 99%

“…31,52 Hif-1α is quickly degraded under normoxic conditions and is nearly undetectable. 31 Therefore, CREB protein which also F I G U R E 4 Upregulating GLUT3 increases mPFC glucose uptake and ameliorates depressive-like behaviors of PSD rats. A, Illustration and representative image shows the adeno-associated virus (AAV)-infected mPFC area in rat brain (upper panel); representative image shows the AAV mainly infect neuron in mPFC (lower panel).…”

Section: Pka/pcreb Signaling Pathway In Ogd/r Treated Primary Neuronsmentioning

confidence: 99%

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Morinda officinalis oligosaccharides ameliorate depressive‐like behaviors in poststroke rats through upregulating GLUT3 to improve synaptic activity

Zhu

Peng

et al. 2020

FASEB j.

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Poststroke depression (PSD) is one of the most common psychiatric diseases afflicting stroke survivors, yet the underlying mechanism is poorly understood. The pathophysiology of PSD is presumably multifactorial, involving ischemia‐induced disturbance in the context of psychosocial distress. The homeostasis of glucose metabolism is crucial to neural activity. In this study, we showed that glucose consumption was decreased in the medial prefrontal cortex (mPFC) of PSD rats. The suppressed glucose metabolism was due to decreased glucose transporter‐3 (GLUT3) expression, the most abundant and specific glucose transporter of neurons. We also found Morinda officinalis oligosaccharides (MOOs), approved as an antidepressive Chinese medicine, through upregulating GLUT3 expression in the mPFC, improved glucose metabolism, and enhanced synaptic activity, which ultimately ameliorated depressive‐like behavior in PSD rats. We further confirmed the mechanism that MOOs induce GLUT3 expression via the PKA/pCREB pathway in PSD rats. Our work showed that MOOs treatment is capable of restoring GLUT3 level to improve depressive‐like behaviors in PSD rats. We also propose GLUT3 as a potential therapeutic target for PSD and emphasize the importance of metabolism disturbance in PSD pathology.

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“…For instance, both Aβ treatment and tau overexpression inhibit CREB phosphorylation with learning and memory deficits (Yin et al, ). As a transcription factor, CREB‐mediated transcription of BDNF is sufficient to promote neuronal dendrite outgrowth, enhance synapse formation, and improve learning and memory (Bu et al, ; Segarra‐Mondejar et al, ). CREB also mediates the transcription of AMPA receptors, which is the molecular basis of excitatory synaptic transmission (Middei et al, ).…”

Section: Introductionmentioning

confidence: 99%

Tau inhibits PKA by nuclear proteasome‐dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation

Yin

Liu

et al. 2019

Aging Cell

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Intraneuronal accumulation of wild-type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear.Here, we report that overexpressing full-length wild-type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse-and memory-associated proteins. Overexpressing hTau inhib its the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP-response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overex pressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ-20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced inter action of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau-induced PKA inhi bition and CREB dephosphorylation, and upregulating PKA improved hTau-induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumula tion induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ-20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition.

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Synaptic activity‐induced glycolysis facilitates membrane lipid provision and neurite outgrowth

Cited by 41 publications

References 91 publications

Brain Fuel Utilization in the Developing Brain

Brain Fuel Utilization in the Developing Brain

Morinda officinalis oligosaccharides ameliorate depressive‐like behaviors in poststroke rats through upregulating GLUT3 to improve synaptic activity

Tau inhibits PKA by nuclear proteasome‐dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation

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