Brain-Derived Neurotrophic Factor Stimulates Energy Metabolism in Developing Cortical Neurons

Burkhalter, Julia; Fiumelli, Hubert; Allaman, Igor; Chatton, Jean–Yves; Martin, Jean‐Luc

doi:10.1523/jneurosci.23-23-08212.2003

Cited by 123 publications

(99 citation statements)

References 59 publications

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“…[35][36][37] The BDNF protein is induced by cortical neurons and regulates survival of striatal neurons in the brain. 38 Several experimental (in vitro and in vivo) and human studies have suggested that BDNF may exacerbate methylmercuryinduced cell death by decreasing the BDNF gene expression. 37,39 Sex-related differences in cord serum BDNF concentrations were observed in relation to prenatal exposure to methylmercury in a Faroese cohort.…”

Section: Discussionmentioning

confidence: 99%

Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

et al. 2013

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Background: Cognitive consequences at school age associated with prenatal methylmercury exposure may need to take into account nutritional and socio-demographic cofactors as well as relevant genetic polymorphisms. Methods: A sub-sample (n = 1311) of the Avon Longitudinal Study of Parents And Children (Bristol, UK) was selected and mercury concentrations were measured in freeze-dried umbilical cord tissue as a measure of methylmercury exposure. A total of 1135 children had available data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) scores at age 8 years. Multivariate regression models were used to assess the associations between methylmercury exposure and IQ and to determine possible gene-environment interactions. Results: Mercury concentrations indicated low background exposures (mean = 26 ng/g, standard deviation = 13). Log-10-transformed mercury was positively associated with IQ, which attenuated after adjustment for nutritional and socio-demographic cofactors. In stratified analyses, a reverse association was found in higher social class families (p-value for interaction = 0.0013, performance IQ), among whom there was a wider range of methylmercury exposure. Among 40 SNPs showing nominally significant main effects, methylmercury interactions were detected for rs662 (Paraoxonase 1) and rs1042838 (Progesterone Receptor) (p < 0.05) and for rs3811647 (Transferrin) and rs2049046 (Brain-Derived Neurotrophic Factor) (p < 0.10). Conclusions: In this population with a low level of methylmercury exposure, there were only equivocal associations between methylmercury exposure and adverse neuropsychological outcomes. Heterogeneities in several relevant genes suggest possible genetic predisposition to methylmercury neurotoxicity in a substantial proportion of the population. Future studies need to address this possibility.

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Section: Discussionmentioning

confidence: 99%

Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

et al. 2013

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“…GLUT-3 possesses higher affinity (lower kilometers) for glucose than GLUT-1 (reviewed in Bolaños et al (2004)). Taking into account the high affinity and dependence of neurons for glucose, it has been postulated that the activity of this transporter would play a beneficial role during glucose deprivation, hypoxic episodes or other metabolic compromising situations (Burant and Bell, 1992;Gerhart et al, 1992;Fattoretti et al, 2001;Burkhalter et al, 2003). Thus, GLUT-3 activity affords neuroprotection (Hara et al, 1989;Lee and Bondy, 1993;Urabe et al, 1996;Uehara et al, 1997), and its malfunctioning is related with neuronal damage (reviewed in McEwen and Reagan (2004)).…”

Section: Discussionmentioning

confidence: 99%

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

García‐Bueno

Caso

Perez‐Nievas

et al. 2006

Neuropsychopharmacol

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Repeated stress causes an energy-compromised status in the brain, with a decrease in glucose utilization by the brain cells, which might account for excitotoxicity processes seen in this condition. In fact, brain glucose metabolism mechanisms are impaired in some neurodegenerative disorders, including stress-related neuropsychopathologies. More recently, it has been demonstrated that some synthetic peroxisome proliferator-activated receptor gamma (PPARg) agonists increase glucose utilization in rat cortical slices and astrocytes, as well as inhibit brain oxidative damage after repeated stress, which add support for considering these drugs as potential neuroprotective agents. To assess if stress causes glucose utilization impairment in the brain and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized for 6 h during 7 or 14 consecutive days, S7, S14) were i.p. injected with the natural ligand 15-deoxy-D-12,14-prostaglandin J 2 (PGJ 2 , 120 mg/kg) or the high-affinity ligand rosiglitazone (RG, 3 mg/kg) at the onset of stress. Repeated immobilization during 1 or 2 weeks produces a decrease in brain cortical synaptosomal glucose uptake, and this effect was prevented by treatment with both natural and synthetic PPARg ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARg ligands prevents stress-induced ATP loss in rat brain. Finally, repeated immobilization stress also produces a decrease in brain cortical synaptosomal glutamate uptake, and this effect was prevented by treatment with PPARg ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ 2 and the thiazolidinedione rosiglitazone increase neuronal glucose metabolism, restore brain ATP levels and prevent the impairment in glutamate uptake mechanisms induced by exposure to stress, suggesting that this class of drugs may be therapeutically useful in conditions in which brain glucose levels or availability are limited after exposure to stress.

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“…Immunocytochemistry-Immunostaining was performed as described previously (13). Cortical neurons were fixed for 20 min in 4% paraformaldehyde except for double-labeling experiments with GABA and MAP2 antibodies where cortical neurons were fixed in a mixture of 4% paraformaldehyde and 0.1% glutaraldehyde.…”

Section: Methodsmentioning

confidence: 99%

“…Western Blotting-Western blots were performed as described previously (13). For immunodetection of SNAT1, SNAT2, hemagglutinin, and ␤-tubulin, blots were incubated overnight at 4°C with an antibody against SNAT1 ( Statistical Analysis-Data were analyzed for statistical significance by using one-way analysis of variance followed by Bonferroni post hoc test except for time course analysis of MeAIB uptake where one-way analysis of variance was followed by Dunnett post hoc test.…”

Section: Methodsmentioning

confidence: 99%

A Critical Role for System A Amino Acid Transport in the Regulation of Dendritic Development by Brain-derived Neurotrophic Factor (BDNF)

Burkhalter

Fiumelli

Erickson

et al. 2007

Journal of Biological Chemistry

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Dendritic development is essential for the establishment of a functional nervous system. Among factors that control dendritic development, brain-derived neurotrophic factor (BDNF) has been shown to regulate dendritic length and complexity of cortical neurons. However, the cellular and molecular mechanisms that underlie these effects remain poorly understood. In this study, we examined the role of amino acid transport in mediating the effects of BDNF on dendritic development. We show that BDNF increases System A amino acid transport in cortical neurons by selective up-regulation of the sodium-coupled neutral amino acid transporter (SNAT)1. Up-regulation of SNAT1 expression and System A activity is required for the effects of BDNF on dendritic growth and branching of cortical neurons. Further analysis revealed that induction of SNAT1 expression and System A activity by BDNF is necessary in particular to enhance synthesis of tissue-type plasminogen activator, a protein that we demonstrate to be essential for the effects of BDNF on cortical dendritic morphology. Together, these data reveal that stimulation of neuronal differentiation by BDNF requires the up-regulation of SNAT1 expression and System A amino acid transport to meet the increased metabolic demand associated with the enhancement of dendritic growth and branching.Development of the nervous system proceeds through a sequence of complex ontogenetic processes that includes cell proliferation, migration, neurite outgrowth, axon guidance, and synapse formation (1). Neuronal development is determined by both intrinsic and extrinsic factors. Among the latter, neurotrophic factors play a key role. In particular, BDNF, 2 a member of the neurotrophin family, controls the survival and differentiation of specific neuronal populations in the peripheral and central nervous system (2). In the developing visual cortex, BDNF has been shown to regulate the dendritic growth and complexity of pyramidal neurons (3, 4). Furthermore, overexpression of BDNF in pyramidal neurons of the visual cortex leads to sprouting of basal dendrites and regression of dendritic spines (5). Because dendritic morphology determines the number, pattern, and types of synapses received by a neuron, regulation of cortical dendritic growth and branching by BDNF is likely to play a major role for the proper functioning of the brain and especially the cerebral cortex.Although BDNF regulates cortical dendritic development, little is known about the cellular and molecular mechanisms underlying these effects. In particular, the role of amino acid transport in mediating the effects of BDNF on dendritic growth and branching remains unknown.System A is a ubiquitous amino acid transport system that mediates the Na ϩ -dependent transport of short-chain neutral amino acids such as alanine, serine, and glutamine (6). In addition, System A is the major amino acid transport system subject to regulation by environmental conditions, proliferative stimuli, developmental changes, hormones, and growth factors (6). Durin...

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Brain-Derived Neurotrophic Factor Stimulates Energy Metabolism in Developing Cortical Neurons

Cited by 123 publications

References 59 publications

Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

Prenatal Methylmercury Exposure and Genetic Predisposition to Cognitive Deficit at Age 8 Years

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

A Critical Role for System A Amino Acid Transport in the Regulation of Dendritic Development by Brain-derived Neurotrophic Factor (BDNF)

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