Biology subjects

Kaulich, E.

Publications and source records attributed to Kaulich, E..

6 recordsLinked to original sources

bioRxiv2025

Brain-wide synaptosome profiling reveals localized mRNAs that diversify synapses

Chemical synapses are the principal communication nodes of the brain, defined by their specialization and plasticity. Their diversity spans multiple levels, from the polarity and magnitude of electrophysiological responses to the proteins driving these differences. Here, we describe another layer of synapse diversity - synaptic transcriptome diversity. Using transgenic mice to fluorescently label presynapses in Camk2a-, Gad2-, DAT-, PV-, SST-, and VIP-expressing neurons, combined with fluorescence-activated synaptosome sorting, we profiled synaptic transcriptomes across five brain regions. We identified [~]4000 mRNAs enriched at synapses - some type-specific, others shared - and highlight region-specific enrichments of mRNAs encoding protein subunits or family members. We found that the abundance of synaptic mRNAs is not a passive reflection of their abundance in cellular somata, indicating active trafficking and sorting mechanisms. Integrating transcriptomic and proteomic data, we identified [~]90 genes with significantly correlated mRNA-protein ratios across regions, mainly involved in synaptic vesicle dynamics, receptor signaling, and calcium regulation, suggesting a key role for local translation in maintaining protein copy number. Although synaptic mRNAs represent only a fraction of the templates for the synaptic proteome, the synaptic transcriptome reflects the synapse diversity captured by the proteome equally well. Together, this dataset (https://syndive.org/) provides a resource for exploring how synaptic mRNA localization and local translation shape synaptic identity and function.

neuroscience↗

bioRxiv2025

Localized mRNAs and protein synthesis in cortical layer 1

Cortical layer 1 plays an essential role for brain function, integrating many streams of information and undergoing synaptic plasticity during learning. Yet, we understand little of the underlying molecular processes, and whether they are specialized to achieve layer-specific functions. Here, we show that layer 1 and its synapses are metabolically active. Using laser capture RNA-sequencing and fluorescence in situ hybridization, we report an abundance of synaptic transcripts localized to layer 1. We purified layer 1 excitatory and inhibitory synapses and characterized their enriched transcriptomes, identifying candidate proteins that can be locally synthesized to maintain and regulate synaptic transmission in layer 1. Furthermore, we find significant differences between the transcriptome of synapses in layer 1 and in deeper, somatic layers, suggesting that local translation might confer specialized function. Finally, by comparing our tissue data with the transcriptome from the hippocampal CA1 strata, we discover a strong similarity between cortical layer 1 and stratum lacunosum moleculare, suggesting that these distal layers share a common molecular environment. Together, our results establish that local protein synthesis is an important mechanism for layer 1, and provide the first comprehensive characterization of the transcripts localized to layer 1 and its synapses.

neuroscience↗

bioRxiv2024

The molecular diversity of hippocampal regions and strata at synaptic resolution revealed by integrated transcriptomic and proteomic profiling

The molecular diversity of neurons and their synapses underlies the different responses and plasticity profiles that drive all neural circuits and behavior. While the extent of this diversity has been partially revealed by transcriptomic and proteomic profiling, combined studies of neuronal transcripts and proteins are limited. Here, we used microdissection of mouse hippocampal subregions and CA1 strata and fluorescence-activated synaptosome sorting (FASS) to characterize the transcripts and proteins from different hippocampal neurons and their compartments with synaptic resolution. Parallel RNA-seq and LC-MS/MS of microdissections identified over 15,000 mRNA transcripts and 10,000 proteins, revealing thousands with local enrichment such as classes of glutamate receptors and voltage-gated potassium channels, myelin-associated molecules, and adhesion molecules. Synaptosome analysis further identified specific enrichment of molecules from collagen, ribosome, solute carrier, and receptor families at different synapses formed along CA1 neurons. By integrating mRNA and protein data, we defined clusters of co-regulated molecules such as adhesion and neurofilament proteins and transporter mRNAs, and found subsets of mRNA-protein pairs with strong correlation and anti-correlation in their abundance variation. Our findings comprise a rich resource on the molecular landscape of the hippocampus and its synapses that is accessible at syndive.org, and highlight the coordinated organization of transcripts and proteins between regions, neuronal compartments, and synapses.

neuroscience↗

bioRxiv2022

Physiological insight into the conserved properties of Caenorhabditis elegans acid-sensing DEG/ENaCs

Acid sensing ion channels (ASICs) are members of the diverse family of degenerin/epithelial sodium channels (DEG/ENaCs). They perform a wide range of physiological roles in healthy organisms, including in gut function and synaptic transmission, but also play important roles in disease, as acidosis is a hallmark of painful inflammatory and ischaemic conditions. We performed a screen for acid-sensitivity on all 30 subunits of the C. elegans DEG/ENaC family using Two-Electrode Voltage Clamp (TEVC) in Xenopus oocytes. We found two groups of acid-sensing DEG/ENaCs characterised by being inhibited or activated by increasing proton concentrations. Three of these acid-sensitive C. elegans DEG/ENaCs were activated by acidic pH, making them functionally similar to the vertebrate ASICs. We also identified four new members of the acid-inhibited DEG/ENaC group, giving a total of seven additional acid-sensitive channels. We observed sensitivity to the anti-hypertensive drug amiloride as well as modulation by the trace element zinc. Acid-sensitive DEG/ENaCs were found to be expressed in both neurons and non-neuronal tissue, highlighting the likely functional diversity of these channels. Our findings provide a framework to exploit the C. elegans channels as models to study the function of these acid-sensing channels in vivo, as well as to study them as potential targets for anti-helminthic drugs.

physiology↗

bioRxiv2021

Distinct roles for two Caenorhabditis elegans acid-sensing ion channels in an ultradian clock

Biological clocks are fundamental to an organisms health, controlling periodicity of behavior and metabolism. Here, we identify two acid-sensing ion channels, with very different proton sensing properties, and describe their role in an ultradian clock, the defecation motor program (DMP) of the nematode Caenorhabditis elegans. An ACD-5-containing channel, on the apical membrane of the intestinal epithelium, is essential for maintenance of luminal acidity, and thus the rhythmic oscillations in lumen pH. In contrast, the second channel, composed of FLR-1, ACD-3 and/or DEL-5, located on the basolateral membrane, controls the intracellular Ca2+ wave and forms a core component of the master oscillator that controls timing and rhythmicity of the DMP. flr-1 and acd-3/del-5 mutants show severe developmental and metabolic defects. We thus directly link the proton-sensing properties of these channels to their physiological roles in pH regulation and Ca2+ signaling, the generation of an ultradian oscillator, and its metabolic consequences. One-Sentence SummaryTwo acid-sensing DEG/ENaC channels play distinct roles in controlling different aspects of rhythmic proton and Ca2+ oscillations in the C. elegans intestine.

physiology↗

bioRxiv2021

The SARS-CoV-2 spike (S) and the orthoreovirus p15 cause neuronal and glial fusion

Numerous enveloped viruses use specialized surface molecules called fusogens to enter host cells1. During virus replication, these fusogens decorate the host cells membrane enabling them the ability to fuse with neighboring cells, forming syncytia that the viruses use to propagate while evading the immune system. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infect the brain and may cause serious neurological symptoms through mechanisms which remain poorly understood2-4. Here we show that expression of either the SARS-CoV-2 spike (S) protein or p15 protein from the baboon orthoreovirus is sufficient to induce fusion between interconnected neurons, as well as between neurons and glial cells. This phenomenon is observed across species, from nematodes to mammals, including human embryonic stem cells-derived neurons and brain organoids. We show that fusion events are progressive, can occur between distant neurites, and lead to the formation of multicellular syncytia. Finally, we reveal that in addition to intracellular molecules, fusion events allow diffusion and movement of large organelles such as mitochondria between fused neurons. Our results provide important mechanistic insights into how SARS-CoV-2 and other viruses could affect the nervous system circuitries causing neurological symptoms.

neuroscience↗