Biology subjects

van Meyel, D.

Publications and source records attributed to van Meyel, D..

3 recordsLinked to original sources

bioRxiv2021

Ataxia-linked SLC1A3 mutations alter EAAT1 chloride channel activity and glial regulation of CNS function

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS). Excitatory Amino Acid Transporters (EAATs) regulate extracellular glutamate by transporting it into cells, mostly glia, to terminate neurotransmission and to avoid neurotoxicity. EAATs are also chloride (Cl-) channels, but the physiological role of Cl- conductance through EAATs is poorly understood. Mutations of human EAAT1 (hEAAT1) have been identified in patients with episodic ataxia type 6 (EA6). One mutation showed increased Cl- channel activity and decreased glutamate transport, but the relative contributions of each function of hEAAT1 to mechanisms underlying the pathology of EA6 remain unclear. Here we investigated the effects of five additional EA6-related mutations on hEAAT1 function in Xenopus laevis oocytes, and on CNS function in a Drosophila melanogaster model of locomotor behavior. Our results indicate that mutations with decreased hEAAT1 Cl- channel activity and functional glutamate transport can also contribute to the pathology of EA6, highlighting the importance of Cl- homeostasis in glial cells for proper CNS function. We also identified a novel mechanism involving an ectopic sodium (Na+) leak conductance in glial cells. Together, these results strongly support the idea that EA6 is primarily an ion channelopathy of CNS glia.

neuroscience↗

bioRxiv2021

A rapid and reliable multiplexed LC-MS/MS method for simultaneous analysis of six monoamines from brain tissues

Monoamines are a class of neuromodulators that are crucial for a variety of brain functions, including control of mood, movement, sleep and cognition. From mammals to insects, the nervous system is enriched in monoamines such as dopamine, serotonin and melatonin, analytes which range from being highly polar to non-polar. Here we developed a method using liquid chromatography coupled with mass spectrometry (LC-MS) to quantify in a single run the amounts of six distinct monoamines in extracts from dissected Drosophila and mouse brain tissues. The measured monoamines were dopamine (DA), serotonin (also known as 5-hydroxytryptamine (5-HT)), octopamine (OA, an insect equivalent of norepinephrine), tyramine (TA), melatonin (MT) and N-acetyl-hydroxy-serotonin (NAS). The analytical range of these monoamines was between 0.25 to 5.0 ng/mL.

neuroscience↗

bioRxiv2019

AANAT1 functions in astrocytes to regulate sleep homeostasis.

Characteristic features of sleep are conserved among species [1], and from humans to insects sleep is influenced by neural circuits involving monoamines such as serotonin and dopamine [2]. Glial cells have been increasingly implicated in mechanisms of baseline and homeostatic sleep regulation in mammals and flies [3-11], but it remains unknown whether and how glia might influence monoaminergic control of sleep. Sleep is regulated by circadian rhythms and a homeostatic drive to compensate for prolonged wakefulness, and growing evidence suggests that neural mechanisms controlling homeostatic sleep can be discriminated from those controlling baseline sleep [12-15]. In Drosophila, mutants of arylalkylamine N-acetyltransferase 1 (AANAT1lo) have normal baseline amounts of sleep and motor activity, but increased rebound sleep following deprivation [16]. AANAT1 can acetylate and inactivate monoamines in vitro [17], but the role of AANAT1 in vivo remains poorly understood. We find AANAT1 to be expressed in astrocytes and subsets of neurons in the adult Drosophila brain, with levels in astrocytes declining markedly overnight. In sleep-deprived AANAT1 mutant flies, heightened rebound sleep is accompanied by increased serotonin and dopamine levels in the brain. In neurons, AANAT1 functions to limit the quantity and consolidation of nighttime sleep, but in astrocytes AANAT1 constrains the amount of rebound sleep that flies take in response to sleep deprivation. These findings distinguish sleep-control functions of AANAT1 in neurons and astrocytes, and identify a critical role for astrocytes in the regulation of monoamine bioavailability and calibration of the response to sleep need.\n\nHighlightsO_LIThe monoamine catabolic enzyme arylalkylamine N-acetyltransferase 1 (AANAT1) is expressed by astrocytes and subsets of serotonergic, glutamatergic, GABAergic and cholinergic neurons in the adult brain of Drosophila.\nC_LIO_LIAANAT1 limits accumulation of serotonin and dopamine in the brain upon sleep deprivation.\nC_LIO_LILoss of AANAT1 from astrocytes, but not from neurons, causes flies to increase their daytime rebound sleep in response to overnight sleep deprivation.\nC_LI

neuroscience↗