The Ammonium-Induced Increase in Rat Brain Lactate Concentration is Rapid and Reversible and is Compatible with Trafficking and Signaling Roles for Ammonium

Provent, Peggy; Kickler, Nils; Barbier, Emmanuel; Bergerot, A; Farion, Régine; Goury, Sarah; Marcaggi, Paı̈kan; Segebarth, Christoph; Coles, Jonathan A.

doi:10.1038/sj.jcbfm.9600480

Cited by 14 publications

(12 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…First, the release of lactate by pure astrocytes in culture during a 1-min exposure to NH + 4 was estimated using an enzymatic assay. Consistent with previous reports (20,23), a significant increase in extracellular lactate was observed at 5 mM NH + 4 . However, the enzymatic assay was unable to detect significant lactate release at 0.2 or 0.5 mM NH + 4 ( Fig.…”

Section: Resultssupporting

confidence: 82%

See 1 more Smart Citation

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Neural activity is accompanied by a transient mismatch between local glucose and oxygen metabolism, a phenomenon of physiological and pathophysiological importance termed aerobic glycolysis. Previous studies have proposed glutamate and K + as the neuronal signals that trigger aerobic glycolysis in astrocytes. Here we used a panel of genetically encoded FRET sensors in vitro and in vivo to investigate the participation of NH + 4 , a by-product of catabolism that is also released by active neurons. Astrocytes in mixed cortical cultures responded to physiological levels of NH + 4 with an acute rise in cytosolic lactate followed by lactate release into the extracellular space, as detected by a lactate-sniffer. An acute increase in astrocytic lactate was also observed in acute hippocampal slices exposed to NH + 4 and in the somatosensory cortex of anesthetized mice in response to i.v. NH + 4 . Unexpectedly, NH + 4 had no effect on astrocytic glucose consumption. Parallel measurements showed simultaneous cytosolic pyruvate accumulation and NADH depletion, suggesting the involvement of mitochondria. An inhibitor-stop technique confirmed a strong inhibition of mitochondrial pyruvate uptake that can be explained by mitochondrial matrix acidification. These results show that physiological NH + 4 diverts the flux of pyruvate from mitochondria to lactate production and release. Considering that NH + 4 is produced stoichiometrically with glutamate during excitatory neurotransmission, we propose that NH + 4 behaves as an intercellular signal and that pyruvate shunting contributes to aerobic lactate production by astrocytes.B rain tissue is almost exclusively energized by the oxidation of glucose. However, during neuronal activation, there is a larger increase in local glucose consumption relative to oxygen consumption (1). As this mismatch occurs in the presence of normal or augmented oxygen levels, it has been termed aerobic glycolysis, paralleling the signal detected by functional magnetic resonance imaging (2). Aerobic glycolysis and its associated lactate surge are causally linked to diverse functions of the brain in health and disease (3-10). Two signals are known to trigger aerobic glycolysis in brain tissue: glutamate and K + , which are released by active neurons and stimulate glycolysis in astrocytes (11,12).Neurons produce as much NH + 4 as they produce glutamate, both molecules being stoichiometrically linked in the glutamateglutamine cycle (13). Brain tissue NH + 4 increases within seconds of neural activation (14-16) and is quickly released to the interstitium (17, 18) to be captured by astrocytes through K + channels and transporters (19). It is well established that chronic exposure to pathological levels of NH + 4 such as those observed during liver failure has a major impact on brain metabolism, but it is not known whether this molecule may affect energy metabolism at physiological levels, particularly within the time scale of synaptic transmission. A previous study showed a reversible rise in brain tissue la...

show abstract

Section: Resultssupporting

confidence: 82%

“…infusion of NH + 4 . In view of this result, NH + 4 was speculated to have signaling roles in the brain (20). The aim of the present work was to investigate this possibility.…”

mentioning

confidence: 97%

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

Lerchundi

Fernández‐Moncada

Contreras-Baeza

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…, ; Provent et al . ). Almost half (10) of the in vivo studies evaluated the effect of systemic administration of lactate (either as an acid or its sodium salt) on CBF in animals.…”

Section: Resultsmentioning

confidence: 97%

“…The majority of in vivo animal studies (Table S3) were conducted in mongrel dogs (Harper and Bell 1963;Iwabuchi et al 1973;Hermansen et al 1984;Young et al 1991), or rats (Hallstr€ om et al 1990;Ido et al 2001Ido et al , 2004Provent et al 2007). Almost half (10) of the in vivo studies evaluated the effect of systemic administration of lactate (either as an acid or its sodium salt) on CBF in animals.…”

Section: In Vivo Studiesmentioning

confidence: 99%

The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

Hollyer

Bordoni

Kousholt

et al. 2019

Journal of Neurochemistry

View full text Add to dashboard Cite

Lactate's role in the brain is understood as a contributor to brain energy metabolism, but it may also regulate the cerebral microcirculation. The purpose of this systematic review was to evaluate evidence of lactate as a physiological effector within the normal cerebral microcirculation in reports ranging from in vitro experiments to in vivo studies in animals and humans. Following pre‐registration of a review protocol, we systematically searched the PubMed, EMBASE , and Cochrane databases for literature covering themes of ‘lactate’, ‘the brain’, and ‘microcirculation’. Abstracts were screened, and data extracted independently by two individuals. We excluded studies evaluating lactate in disease models. Twenty‐eight papers were identified, 18 of which were in vivo animal experiments (65%), four on human studies (14%), and six on in vitro or ex vivo experiments (21%). Approximately half of the papers identified lactate as an augmenter of the hyperemic response to functional activation by a visual stimulus or as an instigator of hyperemia in a dose‐dependent manner, without external stimulation. The mechanisms are likely to be coupled to NAD + / NADH redox state influencing the production of nitric oxide. Unfortunately, only 38% of these studies demonstrated any control for bias, which makes reliable generalizations of the conclusions insecure. This systematic review identifies that lactate may act as a dose‐dependent regulator of cerebral microcirculation by augmenting the hyperemic response to functional activation below 5 mmol/kg, and by initiating a hyperemic response above 5 mmol/kg. Open Science Badges This article has received a badge for * Pre‐registration * because it made the data publicly available. The data can be accessed at www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer_lactate_protocol.aspx . The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/ .

show abstract

“…On the other hand, neurons constantly degrade PFKFB3 (Almeida et al, 2004; and reviewed in Bolaños et al, 2010) and neuronal activation of PFKFB3 was shown to lead to oxidative stress and neuronal apoptosis (Herrero-Mendez et al, 2009). Astrocytic-produced lactate was therefore proposed to alternatively fuel neurons for oxidative metabolism during neuronal activity, in line with stimulation of glycolysis by K + (Peng et al, 1994; Bittner et al, 2011), by glutamate (Pellerin and Magistretti, 1994), and increased lactate efflux by K + (Sotelo-Hitschfeld et al, 2015) and NH +4 (Provent et al, 2007; Lerchundi et al, 2015), while neuronal glucose to be diverted into the pentose phosphate pathway for antioxidant defense during enhanced work at the respiratory chain (Bouzier-Sore and Bolaños, 2015). The study by Sibson et al in the rat brain suggesting 1:1 stoichiometry between neuronal glucose oxidation and the glutamate-glutamine cycle rate (Sibson et al, 1998) provided support to this early view of compartmentation of brain metabolism.…”

Section: Glial Support To Cerebral Functionmentioning

confidence: 93%

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

2017

View full text Add to dashboard Cite

Cerebral function is associated with exceptionally high metabolic activity, and requires continuous supply of oxygen and nutrients from the blood stream. Since the mid-twentieth century the idea that brain energy metabolism is coupled to neuronal activity has emerged, and a number of studies supported this hypothesis. Moreover, brain energy metabolism was demonstrated to be compartmentalized in neurons and astrocytes, and astrocytic glycolysis was proposed to serve the energetic demands of glutamatergic activity. Shedding light on the role of astrocytes in brain metabolism, the earlier picture of astrocytes being restricted to a scaffold-associated function in the brain is now out of date. With the development and optimization of non-invasive techniques, such as nuclear magnetic resonance spectroscopy (MRS), several groups have worked on assessing cerebral metabolism in vivo. In this context, 1H MRS has allowed the measurements of energy metabolism-related compounds, whose concentrations can vary under different brain activation states. 1H-[13C] MRS, i.e., indirect detection of signals from 13C-coupled 1H, together with infusion of 13C-enriched glucose has provided insights into the coupling between neurotransmission and glucose oxidation. Although these techniques tackle the coupling between neuronal activity and metabolism, they lack chemical specificity and fail in providing information on neuronal and glial metabolic pathways underlying those processes. Currently, the improvement of detection modalities (i.e., direct detection of 13C isotopomers), the progress in building adequate mathematical models along with the increase in magnetic field strength now available render possible detailed compartmentalized metabolic flux characterization. In particular, direct 13C MRS offers more detailed dataset acquisitions and provides information on metabolic interactions between neurons and astrocytes, and their role in supporting neurotransmission. Here, we review state-of-the-art MR methods to study brain function and metabolism in vivo, and their contribution to the current understanding of how astrocytic energy metabolism supports glutamatergic activity and cerebral function. In this context, recent data suggests that astrocytic metabolism has been underestimated. Namely, the rate of oxidative metabolism in astrocytes is about half of that in neurons, and it can increase as much as the rate of neuronal metabolism in response to sensory stimulation.

show abstract

The Ammonium-Induced Increase in Rat Brain Lactate Concentration is Rapid and Reversible and is Compatible with Trafficking and Signaling Roles for Ammonium

Cited by 14 publications

References 42 publications

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

NH4+ triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

How Energy Metabolism Supports Cerebral Function: Insights from 13C Magnetic Resonance Studies In vivo

Contact Info

Product

Resources

About