papers

Waller et al 2025

looked at pyruvate kinase in drosophila NMJ

pyk mutants show blocked glycolysis and depleted TCA intermediates

Alessandri et al 2024

HCAR1KO mice are more susceptible to seizures and experience worse seizures

blocking ldha increased recovery time from seizures

Baytas et al 2024

looked at glutamate pyruvate transaminase 2 (GPT2) KO in mice

GPT2 catalyzes glutamate + pyruvate —> alanine + alpha-ketoglutarate

GPT2 KO mice had decreased glutamate release and increased glutamine levels

also observed decreased TCA intermediates but unchanged energetics (ATP levels)

Bredvik and Ryan 2024

compared mitochondrial densities between excitatory and inhibitory neurons

inhibitory neurons have higher mito density and resting ATP levels

loss of MCU (mito calcium uniporter) had effect on inhibitory but not on excitatory neurons

Cueva-Vargas et al 2024

looked at ocular hypertension (risk factor for glaucoma), BRB and mitochondria in the retina

saw that induction of hypertension reduced mitochondrial volume and more fragmented mitochondria

blocking mito fission rescues the volume and reduces oxidative stress

Kadam et al 2024

single mitochondrial sequencing to look at heteroplasy

saw that astrocytic mitos had more SNVs than neuronal mitos

Muñoz- Ballester et al 2024

looks at connexin’s contribution to seizure susceptability after TBI

connexin KO promotes seizures

then further went into channel phosphorylation and different roles of soluble vs membrane-bound connexins

Rauseo et al 2024

mitochondrial lactate production

paper where Matthias & Bruno are on

lactate can be shuttled into mitos

reduced matric & hypoxia stimulates mito lactate production

Sobrido-Cameàn et al 2024

induced heatstress to drosophila NMJ

heatstress reverses electron flow and increased mtROS at complex I

Xie et al 2024

look at tethering between mitos and lysosomes important for mito calcium efflux

one of those tethering proteins is upregulated in seizures and KO of it increases seizure susceptibility in vitro

preventing mitochondrial calcium overload is seizure-protective

Ksendzovsky et al 2023

neuron culture, stimulation leads to ldha upregulation via AMPF/HIF1alpha

say ldha expression occurs preferentially in neurons

ldha expression is increased in brain tissue of patients

Li and Ai 2023

new lactate sensor with subcellular resolution

Miguel Sanz et al 2023

compares zebrafish larval brain structure to mammalian ones

similar in terms of brain regions, cell morphology, neurochemistry and transmitters

Skwarzynska et al 2023

Darias paper

glucose and lactate levels during mouse seizure

saw decrease in EC glucose and rise in lactate

oxamate reduced seizures and improved neuronal survival

Skwarzynska et al 2023 (HCAR1 paper)

HCAR1KO mice are more susceptible to seizure induction

HCAR1 agonists reduce calcium signal from slices

HCAR1 proposed as a high-EC lactate sensor

Yao et al 2023

looks at ldha in a depression mouse model

depressed mice had lower lactate and ldha levels and reduced glycolytic capacity

ldha KO decreases lactate levels and firing rate while lactate perfusion increased the firing rate

Briquet et al 2022

same lab as Abrantes & Alessandri paper

looked at hippocampla brain slices and human epileptic tissue

HCAR expression is increased in human tissue

HCAR1 agonist decreases calcium signals in slices

Rothmann et al 2022

theoretical meta-analysis proposing glycogen as a vital part —> glucose sparing by glycogenolysis

hypothesis: astrocytes use glycogen, so glucose is spared and can be used by neurons

also tested their model against experimental data (including seizure data) and it matches (also ANLS doesn’t match well)

Scott et al 2022

used Laconic in zebrafish to look at wound closure

Banerji et al 2021

follow-up pf Kumar paper (bad zebrafish dravet model)

focus on gluconeogenesis but was confusing

Nasu et al 2021

developed eLACCO1.1

inserted GFP into lactate binding protein from bacteria

Sada et al 2020

lactate and ldh expression in kainate mouse model

increased ldha expression and lactate concentration

ldha inhibitor decreased lactate and attenuates seizures

Tiraboschi et al 2020

dravet model in zebrafish, now focussing on gliosis and GABA interneurons

saw increase in reactive astrocytes and decrease in GABA markers

de Abrantes et al 2019

same Lab as Briquet and Alessandri paper

HCAR1 activation in primary cortical neurons

HCAR1 activation decreases excitability

HCAR1KO neurons had higher basal activity

acts via GPCR (mainly Gi alpha)

Dìaz- Garcia et al 2019

developed SweetieTS

T-sapphire inserted between TtGCP (glucose binding protein from bacteria)

Liu and Baraban 2019

zebrafish epilepsy calcium imaging

Koenig and Dulla 2018

glucose metabolism in seizures following TBI

glycogen stores were depleted in rat seizures after TBI

sub-convulsive stimuli only affected TCA activity in astrocytes while convulsive stimuli affected both cell types

blocking glycolysis but not OXPHOS reduces AP width and amplitude

Malkov et al 2018

seizures are associated with acute oxidative stress and hypoxia

4-AP (increases neuronal activity) causes a drop in glucose and O2 and an increase in lactate

ictal events increased O2 consumption

Hui et al 2017

examined metabolite flux in mice

in the brain, more TCA intermediates are glucose-derived rather than lactate

Nickels and Wirrell 2017

stiripentol (AED) inhibits LDH

Samokhina et al 2017

looked at chronic 2-DG treated rats

chronic 2-DG increases seizure susceptibility and can induce spontaneous seizures

chronic 2-DG reduces glycogen levels and adenosine phosphates but increases mitochondrial metabolism

Forte et al 2016

connects 2-DG to PPP, NADPH and neurosteroids

neurosteroids activate GABAa receptor subunit to hyperpolarize

2-DG evokes outward current partly by GABAa receptors

neurosteroid synthesis is required to mediate the GABA-dependent effect of 2-DG

Jourdain et al 2016

bad excitotoxicity response can be alleviated by lactate & pyruvate but not glucose

hypothesis: ATP production is affected and acts as a signalling molecule on purine receptors

purine receptor inhibition abolished protective effect

Kumar et al 2016

dravet syndrome model in zebrafish but always used entire larvae

say they saw increased glycolysis and no differences in activity of mitochondrial complexes, acitonase, fumarase and malate dehydrogenase

but doesnt really mean anything as they use full larve for all

Kim et al 2015

looked at effect of KD and KB on mito permeability transition pore and LTP in Kcna1 KO mice

KD reduced Kcna1 seizure phenotype

chronic KB treatment of slice cultures elicited spontaneous seizure-like events

activation of mPT resulted in loss of KD-induced seizure control

Sada et al 2015

applied oxamate and AED stiripentol on cultured neurons

oxamate hyperpolarizes neurons which is recoverably by pyruvate, KATP blocker but not lactate

Rueda et al 2015

look at consequences of glutamate-induced excitotoxicity

NMDA receptor activation increases OCR (calcium-dependent OXPHOS boost)

KO of mitochondrial ATP transporter stumps this OXPHOS boost and causes calcium dysregulation

KO of mitochondrial ATP transporters in mice increases seizure susceptibility and astrogliosis

Zhang et al 2015

looked at 13C-labelled acetone & glucose in KD mice

KD decreased cerebral metabolic rate

ketosis (in humans & rats) showed decreased glucose utilization with increased ketosis

Bozzo et al 2013

primary neuron cultures

L-lactate and D-lactate diminished calcium current, reversible by HCAR1 inhibitor

Zhang et al 2013

try to find mechanistic link between anticonvulsive effect and ketosis

ketosis in humans and rats showed reduced glucose utilization

decrease in cerebral metabolic rate correlates with ketosis level & duration

Giménez- Cassina et al 2012

looks at BAD (apoptosis protein that can modulate glucose metabolism) in primary neuron cultures

BAD KO neurons had reduced OCR and maximal respiration that could be rescued by lactate & glutamine but not glucose

BAD KO cultures selectively switch to ketone body utilization

BAD KO mice were resistant to seizures with unaltered system ketone body levels

opening probability of KATP channels was increased in BAD KO neurons

Reid et al 2011

finds a correlation between blood glucose levels and seizure susceptibility

hypoglycemia is enough to induce seizures

Gasior et al 2010

applied 2-DG to different seizure models

saw both pro- and anticonvulsant effects

Gomez-Gonzalo et al 2010

focussed on astrocytic calcium signals and how this can affect neurons using brain slices

triggering astrocytic glutamate release is enough to shift neurons closer to the discharhe threshold

double stimulus of astrocytes causes calcium rise and neuronal discharges in surrounding but also in more distant neurons (and astrocytes)

Stafstorm et al 2009

tested anticonvulsant effect of 2-DG in several acute and chronic rodent seizure models

2-DG can be converted into glycogen and is preferentially taken up by highly metabolically active cells

acute in vivo: saw seizure protection in most protocols

in vitro: lactate, pyruvate and 2-DG reduced induced epileptic bursts

2-DG effect was more long-lasting than lactate & pyruvate

Lian et al 2007

F1,6BP diverts glucose towards PPP and generates glutathione

F1,6BP is anticonvulsant (stronger than 2-DG) and could be partially reversed by lactate

O’Brien et al 2007

activity and kinetics of ldh in astrocytes, synapse cytosol and primary cortical neurons

more ldha in astros, more ldhb in synaptic terminals

L—>P rate is higher in synaptosol vs astros

Simpson et al 2007

GLUT transporter kinetics and role of BBB in supplying glucose

glut3 has higher capacity than others

Garriga-Canut et al 2006

looked at 2-DG-BDNF-TrkB axis

2-DG has seizure-protective effect and lowered BDNF and TrkB expression

mechanism: glycolytic flux affects BDNF repressor (e.g. more glycolytic flux removes repressor while pyruvate & 2-DG increases repression)

Vaillend et al 2002

look at Na-K-ATPase pumps

inhibition of those pumps causes epileptic activity on brain slices

pump blocker increases coupling between EPSPs and spike firing and reduces IPSP amplitudes