Scholars@Duke
Scott Haydn Soderling

Scott Haydn Soderling

George Barth Geller Distinguished Professor of Molecular Biology
Cell Biology
s.soderling@cellbio.duke.edu
Duke Box 3709, Durham, NC 27710
Nanaline Duke Bldg, Durham, NC 27710

Selected Publications

Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions.

Journal Article Nat Commun · August 9, 2024 One of the main drivers of autism spectrum disorder is risk alleles within hundreds of genes, which may interact within shared but unknown protein complexes. Here we develop a scalable genome-editing-mediated approach to target 14 high-confidence autism ri ... Full text Link to item Cite

Presynaptic Rac1 in the hippocampus selectively regulates working memory.

Journal Article Elife · July 24, 2024 One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associat ... Full text Link to item Cite

Training-induced circuit-specific excitatory synaptogenesis in mice is required for effort control.

Journal Article Nat Commun · September 8, 2023 Synaptogenesis is essential for circuit development; however, it is unknown whether it is critical for the establishment and performance of goal-directed voluntary behaviors. Here, we show that operant conditioning via lever-press for food reward training ... Full text Link to item Cite

A Ventromedial Prefrontal-to-Lateral Entorhinal Cortex Pathway Modulates the Gain of Behavioral Responding During Threat.

Journal Article Biol Psychiatry · August 1, 2023 BACKGROUND: The ability to correctly associate cues and contexts with threat is critical for survival, and the inability to do so can result in threat-related disorders such as posttraumatic stress disorder. The prefrontal cortex (PFC) and hippocampus are ... Full text Link to item Cite

Tripartite synaptomics: Cell-surface proximity labeling in vivo.

Journal Article Neurosci Res · December 2021 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 ... Full text Link to item Cite

Cnksr2 Loss in Mice Leads to Increased Neural Activity and Behavioral Phenotypes of Epilepsy-Aphasia Syndrome.

Journal Article J Neurosci · November 17, 2021 Epilepsy Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology. CNKSR2 is a strong X-linked candidate gene implicated in EAS; however, there have been no studies of genetic models to dissect ho ... Full text Link to item Cite

Action potential-coupled Rho GTPase signaling drives presynaptic plasticity.

Journal Article Elife · July 16, 2021 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 ... Full text Link to item Cite

Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans.

Journal Article Elife · March 22, 2021 Mutation of the Wiskott-Aldrich syndrome protein and SCAR homology (WASH) complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revea ... Full text Open Access Link to item Cite

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

Journal Article Nature · December 2020 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. H ... Full text Link to item Cite

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

Journal Article Cell Rep · December 1, 2020 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-throug ... Full text Link to item Cite

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

Journal Article Cell Rep · July 28, 2020 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 transgeni ... Full text Link to item Cite

Essential role for InSyn1 in dystroglycan complex integrity and cognitive behaviors in mice.

Journal Article Elife · December 12, 2019 Human mutations in the dystroglycan complex (DGC) result in not only muscular dystrophy but also cognitive impairments. However, the molecular architecture critical for the synaptic organization of the DGC in neurons remains elusive. Here, we report Inhibi ... Full text Link to item Cite

Plug-and-Play Protein Modification Using Homology-Independent Universal Genome Engineering.

Journal Article Neuron · August 21, 2019 Analysis of endogenous protein localization, function, and dynamics is fundamental to the study of all cells, including the diversity of cell types in the brain. However, current approaches are often low throughput and resource intensive. Here, we describe ... Full text Link to item Cite

Genetically Encoded Fluorescent Indicator GRAPHIC Delineates Intercellular Connections.

Journal Article iScience · May 31, 2019 Intercellular contacts are essential for precise organ morphogenesis, function, and maintenance; however, spatiotemporal information of cell-cell contacts or adhesions remains elusive in many systems. We developed a genetically encoded fluorescent indicato ... Full text Link to item Cite

In vivo proximity proteomics of nascent synapses reveals a novel regulator of cytoskeleton-mediated synaptic maturation.

Journal Article Nat Commun · January 23, 2019 Excitatory synapse formation during development involves the complex orchestration of both structural and functional alterations at the postsynapse. However, the molecular mechanisms that underlie excitatory synaptogenesis are only partially resolved, in p ... Full text Link to item Cite

Identifying Synaptic Proteins by In Vivo BioID from Mouse Brain.

Chapter · 2019 Two anatomically and functionally distinct types of synapses are present in the central nervous system, excitatory synapses, and inhibitory synapses. Purification and analysis of the protein complex at the excitatory postsynapses have led to fundamental in ... Full text Link to item Cite

Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1.

Journal Article J Cell Biol · October 1, 2018 Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug target for epilepsy and neuropathic pain; thus the TSP-α2δ-1 interaction is imp ... Full text Link to item Cite

Regulation of spine structural plasticity by Arc/Arg3.1.

Journal Article Semin Cell Dev Biol · May 2018 Dendritic spines are actin-rich, postsynaptic protrusions that contact presynaptic terminals to form excitatory chemical synapses. These synaptic contacts are widely believed to be the sites of memory formation and information storage, and changes in spine ... Full text Open Access Link to item Cite

Restoring striatal WAVE-1 improves maze exploration performance of GluN1 knockdown mice.

Journal Article PLoS One · 2018 NMDA receptors are important for cognition and are implicated in neuropsychiatric disorders. GluN1 knockdown (GluN1KD) mice have reduced NMDA receptor levels, striatal spine density deficits, and cognitive impairments. However, how NMDA depletion leads to ... Full text Link to item Cite

Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders?

Conference J Neurosci · November 9, 2016 Actin polymerization governs activity-dependent modulation of excitatory synapses, including their morphology and functionality. It is clear from human genetics that neuropsychiatric and neurodevelopmental disturbances are multigenetic in nature, highlight ... Full text Link to item Cite

The Arp2/3 Complex Is Essential for Distinct Stages of Spine Synapse Maturation, Including Synapse Unsilencing.

Journal Article J Neurosci · September 14, 2016 UNLABELLED: Dendritic filopodia are actin-rich structures that are thought to contribute to early spine synapse formation; however, the actin regulatory proteins important for early synaptogenesis are poorly defined. Using organotypic hippocampal slice cul ... Full text Link to item Cite

Identification of an elaborate complex mediating postsynaptic inhibition.

Journal Article Science · September 9, 2016 Inhibitory synapses dampen neuronal activity through postsynaptic hyperpolarization. The composition of the inhibitory postsynapse and the mechanistic basis of its regulation, however, remain poorly understood. We used an in vivo chemico-genetic proximity- ... Full text Link to item Cite

A GABAergic nigrotectal pathway for coordination of drinking behavior.

Journal Article Nat Neurosci · May 2016 The contribution of basal ganglia outputs to consummatory behavior remains poorly understood. We recorded from the substantia nigra pars reticulata (SNR), the major basal ganglia output nucleus, during self-initiated drinking in mice. The firing rates of m ... Full text Link to item Cite

Astrocytes Assemble Thalamocortical Synapses by Bridging NRX1α and NL1 via Hevin.

Journal Article Cell · January 14, 2016 Proper establishment of synapses is critical for constructing functional circuits. Interactions between presynaptic neurexins and postsynaptic neuroligins coordinate the formation of synaptic adhesions. An isoform code determines the direct interactions of ... Full text Link to item Cite

Actin Out: Regulation of the Synaptic Cytoskeleton.

Journal Article J Biol Chem · November 27, 2015 The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at ... Full text Link to item Cite

CNS myelin wrapping is driven by actin disassembly.

Journal Article Dev Cell · July 27, 2015 Myelin is essential in vertebrates for the rapid propagation of action potentials, but the molecular mechanisms driving its formation remain largely unknown. Here we show that the initial stage of process extension and axon ensheathment by oligodendrocytes ... Full text Link to item Cite

Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine.

Journal Article Nat Neurosci · June 2015 Psychiatric and neurodevelopmental disorders may arise from anomalies in long-range neuronal connectivity downstream of pathologies in dendritic spines. However, the mechanisms that may link spine pathology to circuit abnormalities relevant to atypical beh ... Full text Link to item Cite

Astrocytes refine cortical connectivity at dendritic spines.

Journal Article Elife · December 17, 2014 During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. ... Full text Open Access Link to item Cite

Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall.

Journal Article Elife · July 8, 2014 Cdc42 is a signaling protein important for reorganization of actin cytoskeleton and morphogenesis of cells. However, the functional role of Cdc42 in synaptic plasticity and in behaviors such as learning and memory are not well understood. Here we report th ... Full text Link to item Cite

Principles driving the spatial organization of Rho GTPase signaling at synapses

Chapter · May 1, 2014 The Rho proteins play critical roles in numerous aspects of neuronal development, and mutations in their regulators (GEFs and GAPs) and effectors underlie multiple neurodevelopmental and neurological disorders. How Rho GTPase-mediated signaling can have a ... Full text Cite

Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation.

Journal Article Proc Natl Acad Sci U S A · October 1, 2013 The epidermis provides an essential seal from the external environment and retains fluids within the body. To form an effective barrier, cells in the epidermis must form tight junctions and terminally differentiate into cornified envelopes. Here, we demons ... Full text Link to item Cite

Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities.

Journal Article J Neurosci · April 3, 2013 Despite evidence for a strong genetic contribution to several major psychiatric disorders, individual candidate genes account for only a small fraction of these disorders, leading to the suggestion that multigenetic pathways may be involved. Several known ... Full text Link to item Cite

Under lock and key: spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes.

Journal Article Semin Cell Dev Biol · April 2013 WASP family proteins are nucleation promoting factors that bind to and activate the Arp2/3 complex in order to stimulate nucleation of branched actin filaments. The WASP family consists of WASP, N-WASP, WAVE1-3, WASH, and the novel family members WHAMM and ... Full text Link to item Cite

Ultrastructural abnormalities in CA1 hippocampus caused by deletion of the actin regulator WAVE-1.

Journal Article PLoS One · 2013 By conveying signals from the small GTPase family of proteins to the Arp2/3 complex, proteins of the WAVE family facilitate actin remodeling. The WAVE-1 isoform is expressed at high levels in brain, where it plays a role in normal synaptic processing, and ... Full text Link to item Cite

Disruption of wave-associated Rac GTPase-activating protein (Wrp) leads to abnormal adult neural progenitor migration associated with hydrocephalus.

Journal Article J Biol Chem · November 9, 2012 Hydrocephalus is the most common developmental disability and leading cause of brain surgery for children. Current treatments are limited to surgical intervention, as the factors that contribute to the initiation of hydrocephalus are poorly understood. Her ... Full text Link to item Cite

Modified SH2 domain to phototrap and identify phosphotyrosine proteins from subcellular sites within cells.

Journal Article Proc Natl Acad Sci U S A · October 23, 2012 Spatial regulation of tyrosine phosphorylation is important for many aspects of cell biology. However, phosphotyrosine accounts for less than 1% of all phosphorylated substrates, and it is typically a very transient event in vivo. These factors complicate ... Full text Link to item Cite

Peptide array X-linking (PAX): a new peptide-protein identification approach.

Journal Article PLoS One · 2012 Many protein interaction domains bind short peptides based on canonical sequence consensus motifs. Here we report the development of a peptide array-based proteomics tool to identify proteins directly interacting with ligand peptides from cell lysates. Arr ... Full text Link to item Cite

SH3 domain-based phototrapping in living cells reveals Rho family GAP signaling complexes.

Journal Article Sci Signal · November 29, 2011 Rho family GAPs [guanosine triphosphatase (GTPase) activating proteins] negatively regulate Rho family GTPase activity and therefore modulate signaling events that control cytoskeletal dynamics. The spatial distribution of these GAPs and their specificity ... Full text Link to item Cite

Bi-modal regulation of a formin by srGAP2.

Journal Article J Biol Chem · February 25, 2011 The maintenance of rapid and efficient actin dynamics in vivo requires coordination of filament assembly and disassembly. This regulation requires temporal and spatial integration of signaling pathways by protein complexes. However, it remains unclear how ... Full text Link to item Cite

WRP/srGAP3 facilitates the initiation of spine development by an inverse F-BAR domain, and its loss impairs long-term memory.

Journal Article J Neurosci · February 16, 2011 The WAVE-associated Rac GAP, WRP, is thought to regulate key aspects of synapse development and function and may be linked to mental retardation in humans. WRP contains a newly described inverse F-BAR (IF-BAR) domain of unknown function. Our studies show t ... Full text Link to item Cite

Regulation of the postsynaptic cytoskeleton: roles in development, plasticity, and disorders.

Journal Article J Neurosci · November 10, 2010 The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at ... Full text Link to item Cite

Inositol 1,4,5-trisphosphate 3-kinase a functions as a scaffold for synaptic Rac signaling.

Journal Article J Neurosci · November 4, 2009 Activity-dependent alterations of synaptic contacts are crucial for synaptic plasticity. The formation of new dendritic spines and synapses is known to require actin cytoskeletal reorganization specifically during neural activation phases. Yet the site-spe ... Full text Link to item Cite

Mechanisms of cellular protrusions branch out.

Journal Article Dev Cell · September 2009 F-BAR domains bind curved membranes and induce membrane invagination. In a recent Cell paper, Guerrier et al. describe an "inverse" F-BAR family member that induces outward curvature and filopodia in migrating neurons. These findings suggest that F-BAR dom ... Full text Link to item Cite

Grab your partner with both hands: cytoskeletal remodeling by Arp2/3 signaling.

Journal Article Sci Signal · January 27, 2009 The seemingly simple structure of the actin filament belies the elaborate signaling pathways that regulate its assembly and disassembly in eukaryotic cells. In retrospect, this signaling complexity should not be surprising. Actin regulates many dynamic cel ... Full text Link to item Cite

WASP and WAVE Family Protein Complexes

Journal Article · January 1, 2009 Arp2/3 is inactive and is unable to trigger de novo actin polymerization. It must be activated by binding to members of the WASP/WAVE family of scaffold proteins to effectively stimulate actin polymerization. The WASP/WAVE family members (WASP, N-WASP, WAV ... Full text Cite

A WAVE-1 and WRP signaling complex regulates spine density, synaptic plasticity, and memory.

Journal Article J Neurosci · January 10, 2007 The scaffolding protein WAVE-1 (Wiskott-Aldrich syndrome protein family member 1) directs signals from the GTPase Rac through the Arp2/3 complex to facilitate neuronal actin remodeling. The WAVE-associated GTPase activating protein called WRP is implicated ... Full text Link to item Cite

WAVE signalling: from biochemistry to biology.

Journal Article Biochem Soc Trans · February 2006 The small GTPases Rho, Rac and Cdc42 (cell-division cycle 42) function as molecular switches to modulate the actin cytoskeleton. They achieve this by modulating the activity of downstream cellular targets. One group of Rho GTPase effectors, WAVE (Wiskott-A ... Full text Link to item Cite

Identification of a new variant of PDE1A calmodulin-stimulated cyclic nucleotide phosphodiesterase expressed in mouse sperm.

Journal Article Biol Reprod · October 2005 In mature sperm, cAMP plays an important role as a second messenger regulating functions that include capacitation, the acrosome reaction, motility, and, in some cases, chemosensing. We have cloned from mouse testis a novel calmodulin-stimulated cyclic nuc ... Full text Link to item Cite

Bioinformatic design of A-kinase anchoring protein-in silico: a potent and selective peptide antagonist of type II protein kinase A anchoring.

Journal Article Proc Natl Acad Sci U S A · April 15, 2003 Compartmentalization of the cAMP-dependent protein kinase (PKA) is coordinated through association with A-kinase anchoring proteins (AKAPs). A defining characteristic of most AKAPs is a 14- to 18-aa sequence that binds to the regulatory subunits (RI or RII ... Full text Link to item Cite

Loss of WAVE-1 causes sensorimotor retardation and reduced learning and memory in mice.

Journal Article Proc Natl Acad Sci U S A · February 18, 2003 The Scar/WAVE family of scaffolding proteins organize molecular networks that relay signals from the GTPase Rac to the actin cytoskeleton. The WAVE-1 isoform is a brain-specific protein expressed in variety of areas including the regions of the hippocampus ... Full text Link to item Cite

The WRP component of the WAVE-1 complex attenuates Rac-mediated signalling.

Journal Article Nat Cell Biol · December 2002 WAVE-1, which is also known as Scar, is a scaffolding protein that directs actin reorganization by relaying signals from the GTPase Rac to the Arp2/3 complex. Although the molecular details of WAVE activation by Rac have been described, the mechanisms by w ... Full text Link to item Cite

Cloning and characterization of a cAMP-specific phosphodiesterase (TbPDE2B) from Trypanosoma brucei.

Journal Article Proc Natl Acad Sci U S A · April 2, 2002 Here we report the cloning, expression, and characterization of a cAMP-specific phosphodiesterase (PDE) from Trypanosoma brucei (TbPDE2B). Using a bioinformatic approach, two different expressed sequence tag clones were identified and used to isolate the c ... Full text Link to item Cite

Cloning and characterization of two splice variants of human phosphodiesterase 11A.

Journal Article Proc Natl Acad Sci U S A · November 7, 2000 Phosphodiesterase 11A (PDE11A) is a recently identified family of cAMP and cGMP hydrolyzing enzymes. Thus far, a single splice variant designated as PDE11A1 has been reported. In this study, we identify and characterize two additional splice variants of PD ... Full text Link to item Cite

Scar/WAVE-1, a Wiskott-Aldrich syndrome protein, assembles an actin-associated multi-kinase scaffold.

Journal Article EMBO J · September 1, 2000 WAVE proteins are members of the Wiskott-Aldrich syndrome protein (WASP) family of scaffolding proteins that coordinate actin reorganization by coupling Rho-related small molecular weight GTPases to the mobilization of the Arp2/3 complex. We identified WAV ... Full text Link to item Cite

Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions.

Journal Article Curr Opin Cell Biol · April 2000 The past eighteen months have provided much progress in the cyclic nucleotide phosphodiesterase (PDE) field. Six new phosphodiesterase genes have been discovered and characterized. In addition, several new highly specific PDE inhibitors have been developed ... Full text Link to item Cite

Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A.

Journal Article Proc Natl Acad Sci U S A · March 28, 2000 We report here the cloning, expression, and characterization of human PDE11A1, a member of a distinct cyclic nucleotide phosphodiesterase (PDE) family. PDE11A exhibits Full text Link to item Cite

Cloning and characterization of PDE7B, a cAMP-specific phosphodiesterase.

Journal Article Proc Natl Acad Sci U S A · January 4, 2000 A member of the phosphodiesterase (PDE)7 family with high affinity and specificity for cAMP has been identified. Based on sequence homologies, we designate this PDE as PDE7B. The full-length cDNA of PDE7B is 2399 bp, and its ORF sequence predicts a protein ... Full text Link to item Cite

Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A.

Journal Article Proc Natl Acad Sci U S A · June 8, 1999 We report here the cloning, expression, and characterization of a dual-substrate, cAMP and cGMP, cyclic nucleotide phosphodiesterase (PDE) from mouse. This PDE contains the consensus sequence for a PDE catalytic domain, but shares <50% sequence identity wi ... Full text Link to item Cite

Cloning and characterization of a cAMP-specific cyclic nucleotide phosphodiesterase.

Journal Article Proc Natl Acad Sci U S A · July 21, 1998 Cyclic nucleotide phosphodiesterases (PDEs) regulate intracellular levels of cAMP and cGMP by hydrolyzing them to their corresponding 5' monophosphates. We report here the cloning and characterization of a novel cAMP-specific PDE from mouse testis. This un ... Full text Link to item Cite

Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases.

Journal Article J Biol Chem · June 19, 1998 We report the cloning, expression, and characterization of a new family of cyclic nucleotide phosphodiesterase (PDE) that has unique kinetic and inhibitor specificities. A clone corresponding to the C terminus of this PDE was initially identified by a bioi ... Full text Link to item Cite

Identification and characterization of a novel family of cyclic GMP phosphodiesterases

Journal Article NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY · January 1, 1998 Link to item Cite

Characterization of Ca2+/calmodulin-dependent protein kinase IV. Role in transcriptional regulation.

Journal Article J Biol Chem · June 3, 1994 We have characterized Ca2+/calmodulin-dependent protein kinase IV (CaM kinase IV), expressed using the baculovirus/Sf9 cell system, to assess its potential role in Ca2+-dependent transcriptional regulation. CaM kinase IV was strongly inhibited in vitro by ... Link to item Cite