Project

Back to overview

Trans-synaptic signaling in GABAergic synapses (ERC-2014-StG)

English title Trans-synaptic signaling in GABAergic synapses
Applicant Földy Csaba
Number 166815
Funding scheme ERC Transferbeiträge
Research institution Institut für Hirnforschung Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.05.2016 - 30.04.2021
Approved amount 1'618'890.00
Show all

Keywords (3)

Synapse; Transcriptional profiling; Cell-adhesion molecules

Lay Summary (German)

Lead
This project aims to identify cell-type-specific features of neural connectivity in the brain.
Lay summary
Synapses play a key role in the brain by functionally connecting individual neurons as integrated units of pre– and postsynaptic compartments. Within the synapse, there are two principal modes of information exchange: synaptic transmission and trans–synaptic signaling. The first is electrochemical in nature, whereas the latter requires molecular interactions between pre– and postsynaptic synapse adhesion molecules. These two modes operate in parallel, but trans–synaptic signaling is critically required for synaptic transmission because it functionally couples the pre– and postsynaptic complexes. Despite its importance, trans–synaptic signaling is less well understood, because synapse–specific experimental analyses assaying both the electrophysiological and molecular properties of synapse function were previously not available. In the current proposal, I will focus on trans–synaptic interactions that define prominent physiological properties. By using a combination of cutting–edge single cell transcriptional profiling (RNAseq) and synapse–specific electrophysiology in identified GABAergic cells, our overall research aim is to decipher transcriptional information in single cells to predict the molecular physiology of synapses. Results from this project will offer novel insights into the transcriptional determinants of synapse diversity, and reveal fundamental principles of how different synapses accord with neural computations in brain circuits.
Direct link to Lay Summary Last update: 01.03.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Transcriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus
Que Lin, Lukacsovich David, Luo Wenshu, Földy Csaba (2021), Transcriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus, in Nature Communications, 12(1), 108-108.
C1QL3 promotes cell‐cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins
Sticco Matthew J., Peña Palomino Perla A., Lukacsovich David, Thompson Brianna L., Földy Csaba, Ressl Susanne, Martinelli David C. (2021), C1QL3 promotes cell‐cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins, in The FASEB Journal, 35(1), 1.
Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits
Oláh Viktor János, Lukacsovich David, Winterer Jochen, Arszovszki Antónia, Lőrincz Andrea, Nusser Zoltan, Földy Csaba, Szabadics János (2020), Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits, in eLife, 9, 1.
Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors
Cerniauskas Ignas, Winterer Jochen, de Jong Johannes W., Lukacsovich David, Yang Hongbin, Khan Fawwad, Peck James R., Obayashi Sophie K., Lilascharoen Varoth, Lim Byung Kook, Földy Csaba, Lammel Stephan (2019), Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors, in Neuron, 104(5), 899-915.e8.
Single‐cell RNA‐Seq characterization of anatomically identified OLM interneurons in different transgenic mouse lines
Winterer Jochen, Lukacsovich David, Que Lin, Sartori Andrea M., Luo Wenshu, Földy Csaba (2019), Single‐cell RNA‐Seq characterization of anatomically identified OLM interneurons in different transgenic mouse lines, in European Journal of Neuroscience, 50(11), 3750-3771.
Single-Cell RNA-Seq Reveals Developmental Origins and Ontogenetic Stability of Neurexin Alternative Splicing Profiles
Lukacsovich David, Winterer Jochen, Que Lin, Luo Wenshu, Lukacsovich Tamas, Földy Csaba (2019), Single-Cell RNA-Seq Reveals Developmental Origins and Ontogenetic Stability of Neurexin Alternative Splicing Profiles, in Cell Reports, 27(13), 3752-3759.e4.
Deep Survey of GABAergic Interneurons: Emerging Insights From Gene-Isoform Transcriptomics
Que Lin, Winterer Jochen, Földy Csaba (2019), Deep Survey of GABAergic Interneurons: Emerging Insights From Gene-Isoform Transcriptomics, in Frontiers in Molecular Neuroscience, 12, 115.
Single-cell RNAseq reveals cell adhesion molecule profiles in electrophysiologically defined neurons
Földy Csaba, Darmanis Spyros, Aoto Jason, Malenka Robert, Quake Stephen, Südhof Thomas (2016), Single-cell RNAseq reveals cell adhesion molecule profiles in electrophysiologically defined neurons, in PNAS, 113(35), E5222.

Datasets

Single-cell RNAseq reveals cell adhesion molecule profiles in electrophysiologically defined neurons

Author Földy, Csaba; Darmanis, Spyros; Aoto, Jason; Malenka, Robert C.; Quake, Stephen R.; Südhof, Thomas C.
Publication date 30.08.2016
Persistent Identifier (PID) GSE75386
Repository Gene Expression Omnibus (GEO)
Abstract
In brain, signaling mediated by cell adhesion molecules defines the identity and functional properties of synapses. The specificity of presynaptic and postsynaptic interactions that is presumably mediated by cell adhesion molecules suggests that there exists a logic that could explain neuronal connectivity at the molecular level. Despite its importance, however, the nature of such logic is poorly understood, and even basic parameters, such as the number, identity, and single-cell expression profiles of candidate synaptic cell adhesion molecules, are not known. Here, we devised a comprehensive list of genes involved in cell adhesion, and used single-cell RNA sequencing (RNAseq) to analyze their expression in electrophysiologically defined interneurons and projection neurons. We compared the cell type-specific expression of these genes with that of genes involved in transmembrane ion conductances (i.e., channels), exocytosis, and rho/rac signaling, which regulates the actin cytoskeleton. Using these data, we identified two independent, developmentally regulated networks of interacting genes encoding molecules involved in cell adhesion, exocytosis, and signal transduction. Our approach provides a framework for a presumed cell adhesion and signaling code in neurons, enables correlating electrophysiological with molecular properties of neurons, and suggests avenues toward understanding synaptic specificity.

Single-Cell RNA-Seq Reveals Developmental Origins and Ontogenetic Stability of Neurexin Alternative Splicing Profiles

Author Lukacsovich, David; Winterer, Jochen; Que, Lin; Luo, Wenshu; Lukacsovich, Tamas; Földy, Csaba
Publication date 01.06.2019
Persistent Identifier (PID) GSE121653
Repository Gene Expression Omnibus (GEO)


Single‐cell RNA‐Seq characterization of anatomically identified OLM interneurons in different transgenic mouse lines

Author Winterer, Jochen; Lukacsovich, David; Que, Lin; Sartori, Andrea M.; Luo, Wenshu; Földy, Csaba
Publication date 12.09.2019
Persistent Identifier (PID) GSE124847
Repository Gene Expression Omnibus (GEO)


Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors

Author Cerniauskas, Ignas; Winterer, Jochen; de Jong, Johannes W.; Lukacsovich, David; Yang, Hongbin; Khan, Fawwad; Peck, James R.; Obayashi, Sophie K.; Lilascharoen, Varoth; Lim, Byung Kook; Földy, Csaba; Lammel, Stephan
Publication date 01.12.2019
Persistent Identifier (PID) GSE136723
Repository NCBI GEO


Functional specification of CCK+ interneurons by alternative isoforms of Kv4.3 auxiliary subunits

Author Oláh, Viktor János; Lukacsovich, David; Winterer, Jochen; Arszovszki, Antónia; Lőrincz, Andrea; Nusser, Zoltan; Földy, Csaba; Szabadics, János
Publication date 03.06.2020
Persistent Identifier (PID) GSE133951
Repository NCBI GEO
Abstract
CCK-expressing interneurons (CCK+INs) are crucial for controlling hippocampal activity. We found two firing phenotypes of CCK+INs in rat hippocampal CA3 area; either possessing a previously undetected membrane potential-dependent firing or regular firing phenotype, due to different low-voltage-activated potassium currents. These different excitability properties destine the two types for distinct functions, because the former is essentially silenced during realistic 8-15 Hz oscillations. By contrast, the general intrinsic excitability, morphology and gene-profiles of the two types were surprisingly similar. Even the expression of Kv4.3 channels were comparable, despite evidences showing that Kv4.3-mediated currents underlie the distinct firing properties. Instead, the firing phenotypes were correlated with the presence of distinct isoforms of Kv4 auxiliary subunits (KChIP1 vs. KChIP4e and DPP6S). Our results reveal the underlying mechanisms of two previously unknown types of CCK+INs and demonstrate that alternative splicing of few genes, which may be viewed as a minor change in the cells’ whole transcriptome, can determine cell-type identity.

Transcriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus

Author Que, Lin; Lukacsovich, David; Luo, Wenshu; Földy, Csaba
Publication date 04.12.2021
Persistent Identifier (PID) GSE142546
Repository NCBI GEO
Abstract
AbstractThe diversity reflected by >100 different neural cell types fundamentally contributes to brain function and a central idea is that neuronal identity can be inferred from genetic information. Recent large-scale transcriptomic assays seem to confirm this hypothesis, but a lack of morphological information has limited the identification of several known cell types. In this study, we used single-cell RNA-seq in morphologically identified parvalbumin interneurons (PV-INs), and studied their transcriptomic states in the morphological, physiological, and developmental domains. Overall, we find high transcriptomic similarity among PV-INs, with few genes showing divergent expression between morphologically different types. Furthermore, PV-INs show a uniform synaptic cell adhesion molecule (CAM) profile, suggesting that CAM expression in mature PV cells does not reflect wiring specificity after development. Together, our results suggest that while PV-INs differ in anatomy and in vivo activity, their continuous transcriptomic and homogenous biophysical landscapes are not predictive of these distinct identities.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Segerfalk Symposium: "Targeting interneurons in health and disease" Talk given at a conference Single-Cell Transcriptomic Survey of Interneuron Identity and Circuit Connectivity 05.05.2021 Lund (online), Sweden Földy Csaba;
FENS Forum 2020 Talk given at a conference Single-cell trancriptomic survey of neuronal identity and circuit connectivity 11.07.2020 Glasgow (online), Great Britain and Northern Ireland Földy Csaba;
GFC Inhibition in the CNS: Spatio-Temporal Control of GABAergic Signaling and Its Breakdown in Brain Disorders Talk given at a conference Single-Cell Transcriptomic Survey of Interneuron Identity and Circuit Connectivity 07.07.2019 Newry, ME, United States of America Földy Csaba;
3rd Central European Biomedical Congress Talk given at a conference Single-cell transcriptomic survey of neural identity and circuit connectivity 15.09.2018 Krakow, Poland Földy Csaba;
Emerging mechanisms for inhibitory synapse plasticity Talk given at a conference Large-scale single-cellRNAseq data reveals developmental origin of cell adhesion molecules 06.06.2018 Schaffhausen, Switzerland Földy Csaba;
“Synapse Diversity and Complexity” Meeting, Fondation des Treilles, France Talk given at a conference Large-scale single-cell RNAseq data reveals developmental origin of cell adhesion molecules 14.05.2018 Fondation des Treilles, France Földy Csaba;
The Neuronal Surfaceome in Circuit Formation: From Structure to Function Talk given at a conference Large-scale RNAseq data reveals landscape of cell adhesion molecules in diverse cell types 09.07.2017 Anzola d’Ossola, Italy Földy Csaba;


Associated projects

Number Title Start Funding scheme
170085 Physiological and molecular definition of PV interneuron synapses in the hippocampus 01.06.2017 Project funding (Div. I-III)

Abstract

Synapses play a key role in the brain by functionally connecting individual neurons as integrated units of pre- and postsynaptic compartments. Within the synapse, there are two principal modes of information exchange: synaptic transmission and trans-synaptic signaling. The first is electrochemical in nature, whereas the latter requires molecular interactions between pre- and postsynaptic synapse adhesion molecules. These two modes operate in parallel, but trans-synaptic signaling is critically required for synaptic transmission because it functionally couples the pre- and postsynaptic complexes. Despite its importance, trans-synaptic signaling is less well understood, because synapse-specific experimental analyses assaying both the electrophysiological and molecular properties of synapse function were previously not available. In the current proposal, I will focus on novel interactions of the trans-synaptic neuroligin-neurexin complex that define prominent physiological properties. By using a combination of cutting-edge single cell transcriptional profiling (RNAseq) and synapse-specific electrophysiology in identified GABAergic cells, our overall research aim is to decipher transcriptional information in single cells to predict the molecular physiology of synapses. Results from this project will offer novel insights into the transcriptional determinants of synapse diversity, and reveal fundamental principles of how different synapses accord with neural computations in brain circuits.
-