Biology subjects

Van Hameren, G.

Publications and source records attributed to Van Hameren, G..

5 recordsLinked to original sources

bioRxiv2024

Paroxysmal Slow Wave Events as a diagnostic and predictive biomarker for post-traumatic epilepsy

Traumatic brain injury (TBI) is a major global health concern, affecting more than 40 million people annually. While most cases are mild and present with light symptoms, repeated mild injuries can result in delayed brain pathologies, including cognitive decline, neuropsychiatric complications, and post-traumatic epilepsy (PTE). PTE refers to recurring, unprovoked seizures occurring at least one week after TBI. While the link between moderate to severe TBI and PTE is well established, the epileptogenesis after repetitive mild TBI (rmTBI) is seldom studied. Currently, there are no biomarkers to identify those at risk of developing PTE, and its diagnosis is challenging. Here, we used a rat model to study PTE following rmTBI and assessed human EEG data to identify potential biomarkers for PTE. We employed a closed head TBI model to induce rmTBI, and recorded brain activity using electrocorticography (ECoG) between 2- and 6-months post-injury. Behavioral assessments and post-mortem analysis were also conducted. In humans, we analyzed EEG recordings from the Temple University database to investigate the potential of EEG-derived features for diagnosing PTE. At 6 months post injury, 70% of rmTBI animals developed PTE, compared to 22% in the control group (P=0.01). While neurological assessments following injury did not predict PTE, paroxysmal slow wave events (PSWEs) were found to be a reliable biomarker for PTE prediction. In humans, the percentage time in PSWEs was significantly elevated in PTE patients with epileptiform activity. In conclusion, we suggest PSWEs as a non-invasive, cost-effective biomarker for PTE in rodents and human patients.

neuroscience↗

bioRxiv2023

Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury

Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD resulted in neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. Following TBI, CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI. HighlightsCortical spreading depolarization after TBI causes behavioral decline in rats. Vasoconstriction and oligemia after cortical spreading depolarization is worse in TBI brains. Spreading depolarization causes impaired mitochondrial function. TBI and spreading depolarization result in constricted vessels and increased pericyte size. TBI and spreading depolarization result in mitochondrial damage in vascular cells. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/549872v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@176a9a6org.highwire.dtl.DTLVardef@17bfc19org.highwire.dtl.DTLVardef@e3d74dorg.highwire.dtl.DTLVardef@4c194e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Myelinating Schwann cells use Warburg effect to sustain axonal physiology and function

Despite the lactate shuttle theory, how glial cells support axonal metabolism and function remains unclear. Lactate production is a common occurrence following anaerobic glycolysis in muscles. However, several other cell types, including some stem cells, activatezd macrophages and tumor cells, can produce lactate in presence of oxygen and cellular respiration, using Pyruvate Kinase 2 (PKM2) to divert pyruvate to lactate dehydrogenase. We show here that PKM2 is also upregulated in mature myelinating Schwann cells (mSC) of mouse sciatic nerve. Deletion of this isoform in PLP-expressing cells in mice leads to a deficit of lactate in mSC and in peripheral nerves. This had no detectable consequences on the myelin sheath. However, mutant mice developed a peripheral neuropathy. Peripheral nerve axons of mutant mice failed to maintain lactate homeostasis upon activity, resulting in an impaired production of mitochondrial ATP. Action potential propagation was not altered but axonal mitochondria transport was slowed down, muscle axon terminals retracted and motor neurons displayed cellular stress. Additional reduction of lactate availability through dichloroacetate treatment, which diverts pyruvate to mitochondrial oxidative phosphorylation, further aggravated motor dysfunction in mutant mice. Thus, lactate production through aerobic glycolysis is essential in mSC for the long-term maintenance of peripheral nerve axon physiology and function.

neuroscience↗

bioRxiv2019

Schwann cell demyelination is triggered by a transient mitochondrial calcium release through Voltage Dependent Anion Channel 1

The maintenance of the myelin sheath by Schwann cells around peripheral nerve axons is essential for the rapid propagation of action potentials. A large number of peripheral neuropathies results for the loss of this myelin sheath, a process called demyelination. Demyelination is a program of cell dedifferentiation characterized by reprograming and several catabolic and anabolic events. This process was best characterized in Wallerian demyelination that occurs following nerve injury. In this model, the earliest well characterized steps are MAPK pathways activation and cJun phosphorylation and nuclear localization starting around 4hrs after nerve injury. Here we show, using in vivo imaging of virally-delivered fluorescent probes to mitochondria, that Schwann cell mitochondria pH, motility and calcium are altered as soon as 1hr after nerve injury. Mitochondrial calcium release through VDAC1 mitochondrial channel and mPTP directly induced Schwann cell demyelination via MAPK and c-Jun activation. Decreasing mitochondrial calcium release through VDAC1 silencing or TRO19622 blocking prevented MAPK and cJun activation and demyelination. VDAC1 opening with Methyl Jasmonate induced these cellular mechanisms in absence of nerve injury. Taken together, these data indicate that mitochondria calcium homeostasis through VDAC1 is instrumental in the Schwann cell demyelination process and therefore provide a molecular basis for an anti-demyelinating drug approach.

neuroscience↗

bioRxiv2018

Activity-dependent production of ATP and ROS in mitochondria of myelinated axons in healthy and neuropathic conditions

Mitochondria are critical for the function and maintenance of myelinated axons notably through ATP production. A by-product of this activity is reactive oxygen species (ROS), which are highly deleterious for neurons. While ROS and metabolism are involved in several neurodegenerative diseases, it is still unclear how axonal activity or myelin modulates ATP and ROS production in axonal mitochondria. We imaged and quantified mitochondrial ATP and hydrogen peroxide (H2O2) in resting or stimulated peripheral nerve myelinated axons in vivo, using genetically-encoded fluorescent probes, two-photon time-lapse and CARS imaging. ATP and H2O2 productions are intrinsically higher in nodes of Ranvier even in resting conditions. Axonal firing increased both ATP and H2O2 productions but with different dynamics. In neuropathic MFN2R94Q mice, mimicking Charcot-Marie-Tooth 2A disease, defective mitochondria failed to upregulate ATP production following axonal activity. However, H2O2 production was dramatically sustained. Mimicking demyelinating peripheral neuropathy resulted in a reduced production of ATP while H2O2 level soared. Taken together, our results suggest that ATP and ROS productions are decoupled under neuropathic conditions, which may compromise axonal function and integrity.

neuroscience↗