Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse

Abstract

The synapse has high energy demands, which increase during intense activity. Presynaptic ATP production depends on substrate availability and usage will increase during activity, which in turn could influence transmitter release and information transmission. We investigated transmitter release at the mouse calyx of Held synapse using glucose or lactate (10, 1 or 0 mm) as the extracellular substrates while inducing metabolic stress. High frequency stimulation (HFS) and recovery paradigms evoked trains of EPSCs monitored under voltage-clamp. Whilst postsynaptic intracellular ATP was stabilised by diffusion from the patch pipette, depletion of glucose increased EPSC depression during HFS and impaired subsequent recovery. Computational modelling of these data demonstrated a reduction in the number of functional release sites and slowed vesicle pool replenishment during metabolic stress, with little change in release probability. Directly depleting presynaptic terminal ATP impaired transmitter release in an analogous manner to glucose depletion. In the absence of glucose, presynaptic terminal metabolism could utilise lactate from the aCSF and this was blocked by inhibition of monocarboxylate transporters (MCT). MCT inhibitors significantly suppressed transmission in low glucose, implying that lactate is a presynaptic substrate. Additionally, block of glycogenolysis accelerated synaptic transmission failure in the absence of extracellular glucose, consistent with supplemental supply of lactate by local astrocytes. We conclude that both glucose and lactate support presynaptic metabolism and that limited availability, exacerbated by high intensity firing, constrains presynaptic ATP, impeding transmission through a reduction in functional presynaptic release sites as vesicle recycling slows when ATP levels are low.

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Patient, Surgeon, and Anesthesiologist Satisfaction: Who has the Priority?

No abstract available

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Acquired Central Hypoventilation Syndrome Unmasked by Propofol Sedation

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Neurogenic Pulmonary Edema and Stunned Myocardium in a Patient With Meningioma: A Heart-Brain Cross Talk

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Prescribing 6-weeks of running training using parameters from a self-paced maximal oxygen uptake protocol

Abstract

Purpose

The self-paced maximal oxygen uptake test (SPV) may offer effective training prescription metrics for athletes. This study aimed to examine whether SPV-derived data could be used for training prescription.

Methods

Twenty-four recreationally active male and female runners were randomly assigned between two training groups: (1) Standardised (STND) and (2) Self-Paced (S-P). Participants completed 4 running sessions a week using a global positioning system-enabled (GPS) watch: 2 × interval sessions; 1 × recovery run; and 1 × tempo run. STND had training prescribed via graded exercise test (GXT) data, whereas S-P had training prescribed via SPV data. In STND, intervals were prescribed as 6 × 60% of the time that velocity at \(\dot {V}_}}\) ( \(_}\dot {V}_}}\) ) could be maintained (T_max). In S-P, intervals were prescribed as 7 × 120 s at the mean velocity of rating of perceived exertion 20 (_vRPE20). Both groups used 1:2 work:recovery ratio. Maximal oxygen uptake ( \(\dot {V}_}}\) ), \(_}\dot {V}_}}\) , T_{max, v}RPE20, critical speed (CS), and lactate threshold (LT) were determined before and after the 6-week training.

Results

STND and S-P training significantly improved \(\dot {V}_}}\) by 4 ± 8 and 6 ± 6%, CS by 7 ± 7 and 3 ± 3%; LT by 5 ± 4% and 7 ± 8%, respectively (all P < .05), with no differences observed between groups.

Conclusions

Novel metrics obtained from the SPV can offer similar training prescription and improvement in \(\dot {V}_}}\) , CS and LT compared to training derived from a traditional GXT.

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Ethnic Variations in Adiponectin Levels and Its Association with Age, Gender, Body Composition and Diet: Differences Between Iranians, Indians and Europeans Living in Australia

Abstract

Adiponectin is an adipocyte-derived protein with anti-diabetic, anti-atherogenic and anti-inflammatory action, but there are few studies on its association with cardiovascular and metabolic risk factors in different ethnic groups in Australia. This cross-sectional study evaluated ethnic differences in adiponectin levels and its association with age, gender, body composition and diet in 89 adult Australians of European (n = 28), Indian (n = 28) and Iranian (n = 33) ancestries. Different measures of adiposity were assessed using the method of whole body dual energy X-ray absorptiometry (DEXA). Total adiponectin levels determined in Indians and Iranians were significantly lower than those in Europeans (p values < 0.001). There was no significant difference between the adiponectin levels in Indians and Iranians (p value > 0.05). There was no substantial change in the results after adjustment for potential confounders. Circulating levels of adiponectin was associated with age, truncal fat percentage, dietary glycemic index, glycemic load and carbohydrate intake, by correlation analysis (p values < 0.05). Using multiple linear regression analysis, a model including truncal fat percentage (p < 0.001), ethnicity (p = 0.001), age (p = 0.001) and dietary glycemic index (p = 0.04) could predict 50% of the variance in adiponectin levels (R² = 0.504). Among different variables assessed, truncal fat percentage (in Indian and Iranian groups) and glycemic index (in European group) were the strongest predictors of serum adiponectin when data were analysed for three ethnic groups, separately. In conclusion, individuals with Iranian or Indian ancestries may have lower adiponectin levels compared to Europeans. Ethnicity was found as an independent factor affecting adiponectin levels. Our results also highlighted age, truncal adiposity and dietary glycemic index as other determinants of serum adiponectin, however the extent to which these factors influence adiponectin concentrations may vary across ethnicities.

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The cells and conductance mediating cholinergic neurotransmission in the murine proximal stomach

Abstract

Enteric motor neurotransmission is essential for normal gastrointestinal (GI) motility. Controversy exists regarding the cells and ionic conductance(s) that mediate post-junctional neuroeffector responses to motor neurotransmitters. Isolated intramuscular ICC (ICC-IM) and smooth muscle cells (SMCs) from murine fundus muscles were used to determine the conductances activated by carbachol (CCh) in each cell-type. The calcium-activated chloride conductance (CaCC), Ano1 is expressed by ICC-IM but not resolved in SMCs, and CCh activated a Cl⁻ conductance in ICC-IM and a non-selective cation conductance (NSCC) in SMCs. We also studied responses to nerve stimulation using electrical-field stimulation (EFS) of intact fundus muscles from wildtype and Anoctamin-1 (Ano1) knockout mice. EFS activated excitatory junction potentials (EJPs) in wildtype mice, but EJPs were absent in mice with congenital deactivation of Ano1 and greatly reduced in animals in which the CaCC-Ano1 was knocked down using the Cre/loxP technology. Contractions to cholinergic nerve stimulation were also greatly reduced in Ano1 knockouts. SMCs cells also have receptors and ion channels activated by muscarinic agonists. Blocking acetylcholine esterase with neostigmine revealed a slow depolarization that developed after EJPs in wildtype mice. This depolarization was still apparent in mice with genetic deactivation of Ano1. Pharmacological blockers of Ano1 also inhibited EJPs and contractile responses to muscarinic stimulation in fundus muscles Our data are consistent with the hypothesis that ACh released from motor nerves binds muscarinic receptors on ICC-IM with preference and activates Ano1. If metabolism of is inhibited, ACh overflows and binds to extrajunctional receptors on SMCs, eliciting a slower depolarization response.

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