Biology subjects

Niklaus, S.

Publications and source records attributed to Niklaus, S..

4 recordsLinked to original sources

bioRxiv2024

Characterization of Postsynaptic Glutamate Transporter Functionality in the Zebrafish Retinal First Synapse Across Different Wavelengths

In the zebrafish retina, incident light undergoes wavelength-dependent processing encompassing mechanisms such as color opponency, contrast enhancement, and motion detection prior to neural transmission to the brain proper. In darkness, photoreceptors continuously release glutamate into the synaptic cleft, a process that diminishes in response to increased light intensity, thereby conveying visual signals to ON and OFF bipolar cells. Specifically, in zebrafish, the ON pathway signal transduction is mediated by metabotropic glutamate receptor 6b (mGluR6b) and Excitatory Amino Acid Transporters (EAATs). Here we demonstrate that knockout of eaat5b and eaat7 disrupts electroretinogram responses to short and long-wavelength stimuli while preserving middlewavelength responses, suggesting wavelength-specific roles. We found differential expression of EAAT5b and EAAT7 in the outer plexiform layer, particularly in the strike zone, crucial for prey capture, supporting task specific involvement of these signaling pathways. In order to investigate this, we developed a virtual hunting assay using UV light stimuli. Such a behavioral assay targeting short and long wavelengths indicate that EAAT5b and EAAT7 influence UV-dependent prey detection and motion sensing differently. Our findings highlight the importance of EAAT5b and EAAT7 in modulating light integration dynamics in the zebrafish retina.

neuroscience↗

bioRxiv2023

Glutamate Transporters are Involved in Direct Inhibitory Synaptic Transmission in the Vertebrate Retina

In the central nervous system of vertebrates, glutamate serves as the primary excitatory neurotransmitter. However, in the retina, glutamate released from photoreceptors causes hyperpolarization in postsynaptic ON-bipolar cells through a glutamate-gated chloride current, which seems paradoxical. Our research reveals that this current is modulated by two excitatory glutamate transporters, EAAT5b and EAAT7. These transporters are located at the dendritic tips of ON-bipolar cells and interact with all four types of cone photoreceptors. The absence of these transporters leads to a decrease in ON-bipolar cell responses, with eaat5b mutants being more severely affected than eaat5b/eaat7 double mutants, which also exhibit altered response kinetics. Biophysical investigations establish that EAAT7 is an active glutamate transporter with a predominant anion conductance. Our study is the first to demonstrate the direct involvement of postsynaptic glutamate transporters in inhibitory direct synaptic transmission at a central nervous system synapse.

neuroscience↗

bioRxiv2021

Loss of the glial glutamate transporter eaat2a leads to a combined developmental and epileptic encephalopathy in zebrafish

Astroglial excitatory amino acid transporter 2 (EAAT2, GLT-1, SLC1A2) regulates the duration and extent of neuronal excitation by removing glutamate from the synaptic cleft. Hence, an impairment in EAAT2 function could lead to an imbalanced neural network excitability. Here, we investigated the functional alterations of neuronal and astroglial networks associated with the loss of function in the astroglia predominant eaat2a gene in zebrafish. We observed that eaat2a-/- mutant zebrafish larvae display recurrent spontaneous and light-induced seizures in neurons and astroglia, which coincide with an abrupt increase in extracellular glutamate levels. In stark contrast to this hyperexcitability, basal neuronal and astroglial activity was surprisingly reduced in eaat2a-/- mutant animals, which manifested in decreased overall locomotion. Our results reveal an essential and mechanistic contribution of EAAT2a in balancing brain excitability, and its direct link to epileptic seizures.

neuroscience↗

bioRxiv2020

Loss of slc39a14 causes simultaneous manganese deficiency and hypersensitivity in zebrafish

Mutations in SLC39A14, a manganese uptake transporter, lead to a neurodegenerative disorder characterised by accumulation of manganese in the brain and rapidly progressive dystonia-parkinsonism (Hypermanganesemia with Dystonia 2, HMNDYT2). Similar to the human phenotype, zebrafish slc39a14U801-/- mutants show prominent brain manganese accumulation and abnormal locomotor behaviour. In order to identify novel potential targets of manganese neurotoxicity, we performed transcriptome analysis of individual homozygous mutant and sibling slc39a14U801 zebrafish at five days post fertilisation unexposed and exposed to MnCl2. Anatomical gene enrichment analysis confirmed that differentially expressed genes map to the central nervous system and eye. Biological interpretation of differentially expressed genes suggests that calcium dyshomeostasis, activation of the unfolded protein response, oxidative stress, mitochondrial dysfunction, lysosomal disruption, apoptosis and autophagy, and interference with proteostasis are key events in manganese neurotoxicity. Differential expression of visual phototransduction genes also predicted visual dysfunction in mutant larvae which was confirmed by the absence of visual background adaptation and a diminished optokinetic reflex. Surprisingly, we found a group of differentially expressed genes in mutant larvae that normalised upon MnCl2 treatment suggesting that, in addition to neurotoxicity, manganese deficiency is present either subcellularly or in specific cells or tissues. This may have important implications for treatment as manganese chelation may aggravate neurological symptoms. Our analyses show that slc39a14U801-/- mutant zebrafish present a powerful model to study the cellular and molecular mechanisms underlying disrupted manganese homeostasis. Significance statementManganese neurotoxicity leading to progressive dystonia-parkinsonism is a characteristic feature of Hypermanganesemia with dystonia 2 (HMNDYT2) caused by mutations in SLC39A14, a manganese uptake transporter. Transcriptional profiling in slc39a14U801 loss-of-function zebrafish suggests that, in addition to manganese neurotoxicity, subcellular or cell type specific manganese deficiency contributes to the disease phenotype. Both manganese overload and deficiency appear to be associated with Ca2+ dyshomeostasis. We further demonstrate that activation of the unfolded protein response, oxidative stress, mitochondrial dysfunction, apoptosis and autophagy, and disrupted proteostasis are likely downstream events in manganese neurotoxicity. Our study shows that the zebrafish slc39a14U801 loss-of-function mutant is a powerful model to elucidate the mechanistic basis of diseases affected by manganese dyshomeostasis.

neuroscience↗