Scott Soderling

Positions:

George Barth Geller Distinguished Professor of Molecular Biology

Cell Biology
School of Medicine

Professor in Cell Biology

Cell Biology
School of Medicine

Chair, Department of Cell Biology

Cell Biology
School of Medicine

Professor of Neurobiology

Neurobiology
School of Medicine

Faculty Network Member of the Duke Institute for Brain Sciences

Duke Institute for Brain Sciences
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1999

University of Washington

Postdoctoral Fellow, Hhmi

Oregon Health and Science University

Grants:

How Does Huntingtin Control Synaptic Development?

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

Control of cell fate by progenitor mitosis length and microcephaly-linked genes during cortical development

Administered By
Molecular Genetics and Microbiology
Awarded By
National Institutes of Health
Role
Co-Sponsor
Start Date
End Date

Interrogating the role of the novel synaptic protein Rogdi in GABAergic inhibition and epilepsy

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Analysis of Inhibitory Synaptic Proteins Associated with Brain Disorders

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Interneuron Synapses: In Vivo Chemicogenetic Proteomics to Discover Developmental Brain Disorder Etiologies

Administered By
Cell Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

Tripartite synaptomics: Cell-surface proximity labeling in vivo.

The astrocyte is a central glial cell and plays a critical role in the architecture and activity of neuronal circuits and brain functions through forming a tripartite synapse with neurons. Emerging evidence suggests that dysfunction of tripartite synaptic connections contributes to a variety of psychiatric and neurodevelopmental disorders. Furthermore, recent advancements with transcriptome profiling, cell biological and physiological approaches have provided new insights into the molecular mechanisms into how astrocytes control synaptogenesis in the brain. In addition to these findings, we have recently developed in vivo cell-surface proximity-dependent biotinylation (BioID) approaches, TurboID-surface and Split-TurboID, to comprehensively understand the molecular composition between astrocytes and neuronal synapses. These proteomic approaches have discovered a novel molecular framework for understanding the tripartite synaptic cleft that arbitrates neuronal circuit formation and function. Here, this short review highlights novel in vivo cell-surface BioID approaches and recent advances in this rapidly evolving field, emphasizing how astrocytes regulate excitatory and inhibitory synapse formation in vitro and in vivo.
Authors
Takano, T; Soderling, SH
MLA Citation
Takano, Tetsuya, and Scott H. Soderling. “Tripartite synaptomics: Cell-surface proximity labeling in vivo.Neurosci Res, May 2021. Pubmed, doi:10.1016/j.neures.2021.05.002.
URI
https://scholars.duke.edu/individual/pub1482956
PMID
34019951
Source
pubmed
Published In
Neurosci Res
Published Date
DOI
10.1016/j.neures.2021.05.002

Action potential-coupled Rho GTPase signaling drives presynaptic plasticity.

In contrast to their postsynaptic counterparts, the contributions of activity-dependent cytoskeletal signaling to presynaptic plasticity remain controversial and poorly understood. To identify and evaluate these signaling pathways, we conducted a proteomic analysis of the presynaptic cytomatrix using in vivo biotin identification (iBioID). The resultant proteome was heavily enriched for actin cytoskeleton regulators, including Rac1, a Rho GTPase that activates the Arp2/3 complex to nucleate branched actin filaments. Strikingly, we find Rac1 and Arp2/3 are closely associated with synaptic vesicle membranes in adult mice. Using three independent approaches to alter presynaptic Rac1 activity (genetic knockout, spatially restricted inhibition, and temporal optogenetic manipulation), we discover that this pathway negatively regulates synaptic vesicle replenishment at both excitatory and inhibitory synapses, bidirectionally sculpting short-term synaptic depression. Finally, we use two-photon fluorescence lifetime imaging to show that presynaptic Rac1 activation is coupled to action potentials by voltage-gated calcium influx. Thus, this study uncovers a previously unrecognized mechanism of actin-regulated short-term presynaptic plasticity that is conserved across excitatory and inhibitory terminals. It also provides a new proteomic framework for better understanding presynaptic physiology, along with a blueprint of experimental strategies to isolate the presynaptic effects of ubiquitously expressed proteins.
Authors
O'Neil, SD; Rácz, B; Brown, WE; Gao, Y; Soderblom, EJ; Yasuda, R; Soderling, SH
MLA Citation
O’Neil, Shataakshi Dube, et al. “Action potential-coupled Rho GTPase signaling drives presynaptic plasticity.Elife, vol. 10, July 2021. Pubmed, doi:10.7554/eLife.63756.
URI
https://scholars.duke.edu/individual/pub1488670
PMID
34269176
Source
pubmed
Published In
Elife
Volume
10
Published Date
DOI
10.7554/eLife.63756

Master Regulators and Cofactors of Human Neuronal Cell Fate Specification Identified by CRISPR Gene Activation Screens.

Technologies to reprogram cell-type specification have revolutionized the fields of regenerative medicine and disease modeling. Currently, the selection of fate-determining factors for cell reprogramming applications is typically a laborious and low-throughput process. Therefore, we use high-throughput pooled CRISPR activation (CRISPRa) screens to systematically map human neuronal cell fate regulators. We utilize deactivated Cas9 (dCas9)-based gene activation to target 1,496 putative transcription factors (TFs) in the human genome. Using a reporter of neuronal commitment, we profile the neurogenic activity of these factors in human pluripotent stem cells (PSCs), leading to a curated set of pro-neuronal factors. Activation of pairs of TFs reveals neuronal cofactors, including E2F7, RUNX3, and LHX8, that improve conversion efficiency, subtype specificity, and maturation of neuronal cell types. Finally, using multiplexed gene regulation with orthogonal CRISPR systems, we demonstrate improved neuronal differentiation with concurrent activation and repression of target genes, underscoring the power of CRISPR-based gene regulation for programming complex cellular phenotypes.
Authors
Black, JB; McCutcheon, SR; Dube, S; Barrera, A; Klann, TS; Rice, GA; Adkar, SS; Soderling, SH; Reddy, TE; Gersbach, CA
MLA Citation
Black, Joshua B., et al. “Master Regulators and Cofactors of Human Neuronal Cell Fate Specification Identified by CRISPR Gene Activation Screens.Cell Rep, vol. 33, no. 9, Dec. 2020, p. 108460. Pubmed, doi:10.1016/j.celrep.2020.108460.
URI
https://scholars.duke.edu/individual/pub1466974
PMID
33264623
Source
pubmed
Published In
Cell Reports
Volume
33
Published Date
Start Page
108460
DOI
10.1016/j.celrep.2020.108460

Chemico-genetic discovery of astrocytic control of inhibition in vivo.

Perisynaptic astrocytic processes are an integral part of central nervous system synapses1,2; however, the molecular mechanisms that govern astrocyte-synapse adhesions and how astrocyte contacts control synapse formation and function are largely unknown. Here we use an in vivo chemico-genetic approach that applies a cell-surface fragment complementation strategy, Split-TurboID, and identify a proteome that is enriched at astrocyte-neuron junctions in vivo, which includes neuronal cell adhesion molecule (NRCAM). We find that NRCAM is expressed in cortical astrocytes, localizes to perisynaptic contacts and is required to restrict neuropil infiltration by astrocytic processes. Furthermore, we show that astrocytic NRCAM interacts transcellularly with neuronal NRCAM coupled to gephyrin at inhibitory postsynapses. Depletion of astrocytic NRCAM reduces numbers of inhibitory synapses without altering glutamatergic synaptic density. Moreover, loss of astrocytic NRCAM markedly decreases inhibitory synaptic function, with minor effects on excitation. Thus, our results present a proteomic framework for how astrocytes interface with neurons and reveal how astrocytes control GABAergic synapse formation and function.
Authors
Takano, T; Wallace, JT; Baldwin, KT; Purkey, AM; Uezu, A; Courtland, JL; Soderblom, EJ; Shimogori, T; Maness, PF; Eroglu, C; Soderling, SH
MLA Citation
Takano, Tetsuya, et al. “Chemico-genetic discovery of astrocytic control of inhibition in vivo.Nature, vol. 588, no. 7837, Dec. 2020, pp. 296–302. Pubmed, doi:10.1038/s41586-020-2926-0.
URI
https://scholars.duke.edu/individual/pub1465335
PMID
33177716
Source
pubmed
Published In
Nature
Volume
588
Published Date
Start Page
296
End Page
302
DOI
10.1038/s41586-020-2926-0

Dysregulation of the Synaptic Cytoskeleton in the PFC Drives Neural Circuit Pathology, Leading to Social Dysfunction.

Psychiatric disorders are highly heritable pathologies of altered neural circuit functioning. How genetic mutations lead to specific neural circuit abnormalities underlying behavioral disruptions, however, remains unclear. Using circuit-selective transgenic tools and a mouse model of maladaptive social behavior (ArpC3 mutant), we identify a neural circuit mechanism driving dysfunctional social behavior. We demonstrate that circuit-selective knockout (ctKO) of the ArpC3 gene within prefrontal cortical neurons that project to the basolateral amygdala elevates the excitability of the circuit neurons, leading to disruption of socially evoked neural activity and resulting in abnormal social behavior. Optogenetic activation of this circuit in wild-type mice recapitulates the social dysfunction observed in ArpC3 mutant mice. Finally, the maladaptive sociability of ctKO mice is rescued by optogenetically silencing neurons within this circuit. These results highlight a mechanism of how a gene-to-neural circuit interaction drives altered social behavior, a common phenotype of several psychiatric disorders.
Authors
Kim, IH; Kim, N; Kim, S; Toda, K; Catavero, CM; Courtland, JL; Yin, HH; Soderling, SH
MLA Citation
Kim, Il Hwan, et al. “Dysregulation of the Synaptic Cytoskeleton in the PFC Drives Neural Circuit Pathology, Leading to Social Dysfunction.Cell Rep, vol. 32, no. 4, July 2020, p. 107965. Pubmed, doi:10.1016/j.celrep.2020.107965.
URI
https://scholars.duke.edu/individual/pub1454010
PMID
32726629
Source
pubmed
Published In
Cell Reports
Volume
32
Published Date
Start Page
107965
DOI
10.1016/j.celrep.2020.107965

Research Areas:

3',5'-Cyclic-AMP Phosphodiesterases
3',5'-Cyclic-GMP Phosphodiesterases
Actin Cytoskeleton
Actin-Related Protein 2-3 Complex
Actins
Alternative Splicing
Amino Acid Sequence
Animals
Animals, Newborn
Avoidance Learning
Bacterial Proteins
Base Sequence
Binding Sites
Blotting, Northern
Blotting, Southern
Brain
Brain Chemistry
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Catalysis
Cell Compartmentation
Cell Line
Cell Membrane
Cell Movement
Cell Polarity
Cells, Cultured
Cercopithecus aethiops
Cerebral Ventricles
Chromosomes, Artificial, Bacterial
Cloning, Molecular
Computational Biology
Consensus Sequence
Cyclic AMP
Cyclic AMP-Dependent Protein Kinase Type II
Cyclic AMP-Dependent Protein Kinases
Cyclic GMP
Cyclic Nucleotide Phosphodiesterases, Type 1
Cyclic Nucleotide Phosphodiesterases, Type 7
Cytoskeletal Proteins
Cytoskeleton
DNA, Complementary
Databases as Topic
Dendritic Spines
Dimerization
Disease Models, Animal
Endocytosis
Enzyme Inhibitors
Epidermis
Exploratory Behavior
Expressed Sequence Tags
Fertility
Fluorescent Dyes
GTPase-Activating Proteins
Gene Deletion
Gene Expression
Gene Expression Regulation
Gene Expression Regulation, Developmental
Genetic Variation
Green Fluorescent Proteins
HEK293 Cells
HeLa Cells
Hippocampus
Homeostasis
Humans
Hydrocephalus
Immunohistochemistry
In Situ Hybridization, Fluorescence
Indoles
Insulin
Intracellular Signaling Peptides and Proteins
Isoenzymes
Keratinocytes
Kinetics
Learning
Lipid Metabolism
Liposomes
Luminescent Proteins
Lymphocyte Activation
Macrophages
Magnetic Resonance Imaging
Male
Mass Spectrometry
Matrix Attachment Regions
Maze Learning
Memory
Memory Disorders
Mental Disorders
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Microarray Analysis
Microfilament Proteins
Microscopy, Electron
Microscopy, Electron, Scanning
Models, Biological
Models, Chemical
Models, Molecular
Molecular Sequence Data
Molecular Weight
Motor Activity
Multiprotein Complexes
Nerve Tissue Proteins
Neuronal Plasticity
Neurons
Neuropsychological Tests
Open Reading Frames
Organic Chemicals
Penile Erection
Peptide Fragments
Peptide Library
Peptide Mapping
Phosphatidylinositols
Phosphoproteins
Phosphoric Diester Hydrolases
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor)
Photobleaching
Potassium Channels
Presynaptic Terminals
Protein Binding
Protein Conformation
Protein Engineering
Protein Interaction Domains and Motifs
Protein Isoforms
Protein Structure, Tertiary
Proteins
Proteomics
RNA, Messenger
RNA, Untranslated
Rats
Rats, Sprague-Dawley
Receptors, GABA-A
Receptors, Glutamate
Recombinant Proteins
Reflex, Startle
Restriction Mapping
Sensation
Sequence Alignment
Sequence Homology, Amino Acid
Signal Transduction
Social Behavior
Sperm Motility
Sperm Tail
Spermatozoa
Startle Reaction
Stem Cells
Subcellular Fractions
Substrate Specificity
Synapses
Synaptic Transmission
T-Lymphocytes
Testis
Thiophenes
Time Factors
Wiskott-Aldrich Syndrome
Wiskott-Aldrich Syndrome Protein Family
rac GTP-Binding Proteins
rac1 GTP-Binding Protein
src Homology Domains