About

Richard Huganir is a Bloomberg Distinguished Professor in the Department of Neuroscience at the Johns Hopkins University School of Medicine and the Department of Psychological and Brain Sciences at the Krieger School of Arts and Sciences. He serves as the Director of the Solomon H. Snyder Department of Neuroscience and is also Co-Director of the Johns Hopkins Brain Science Institute. His research interests focus on the molecular and cellular mechanisms that regulate neurotransmitter receptors and synapse function. Huganir completed his undergraduate work in biochemistry at Vassar College and earned his Ph.D. in Biochemistry, Molecular and Cell Biology from Cornell University, where he conducted thesis research in the laboratory of Efraim Racker. Following a postdoctoral fellowship at Yale University School of Medicine in Paul Greengard's laboratory, he joined the faculty of Rockefeller University as an Assistant Professor of Molecular and Cellular Neuroscience. Currently, he is a professor and director at Johns Hopkins University, contributing significantly to the understanding of synaptic mechanisms and neurotransmitter receptor regulation.

Research topics

• Computer Science
• Biology
• Neuroscience
• Genetics
• Evolutionary biology
• Computational biology

Selected publications

• DELTA: a method for brain-wide measurement of synaptic protein turnover reveals localized plasticity during learning

  Nature Neuroscience · 2025-03-31 · 21 citations

  articleOpen access

  Synaptic plasticity alters neuronal connections in response to experience, which is thought to underlie learning and memory. However, the loci of learning-related synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown. Here we describe a new method, DELTA, for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor subunit GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly hippocampal area CA1. More broadly distributed increases in the turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input-specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of plasticity at scales ranging from single synapses to the entire brain.

  PublisherOA PDFDOI

• Syngap1 and the development of murine neocortical progenitor cells

  Nature Communications · 2025-12-11 · 2 citations

  articleOpen accessSenior author

  SYNGAP1 regulates synaptic plasticity through interactions with scaffold proteins and modulation of Ras and Rap GTPase signaling. Human SYNGAP1 mutations are linked to intellectual disability, epilepsy, and autism. In mice, Syngap1 haploinsufficiency causes impaired LTP, premature maturation of dendritic spines, learning disabilities, and seizures, reflecting the human phenotypes of SYNGAP1 syndrome. Recently, SYNGAP1 was shown to influence cortical neurogenesis and progenitor proliferation in human organoids. Here, we show that Syngap1 absence or haploinsufficiency does not alter neocortical progenitors and their cellular output in mice. Despite careful analysis of cortical progenitor properties, we fail to replicate the main findings from human organoids. This discrepancy suggests species-specific or methodological differences and raises questions about the broader relevance of SYNGAP1’s role in neurogenesis. The absence of cortical progenitor deficits in haploinsufficient mice, which exhibit cognitive deficits and seizures, indicates these arise from SYNGAP1’s regulation of synapse function rather than its role on neurogenesis. Here authors report Syngap1 loss or reduction in mice does not affect cortical progenitors, unlike in human organoids. This suggests some species-specific differences but still supports synaptic dysfunction as the most probable cause of SYNGAP1-related disorders.

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• Loss of the proton-activated chloride channel in neurons impairs AMPA receptor endocytosis and LTD via endosomal hyper-acidification

  Cell Reports · 2025-02-01 · 8 citations

  articleOpen access

  Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are forms of synaptic plasticity, thought to be the molecular basis of learning and memory, dependent on dynamic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Alteration of endosomal pH negatively affects synaptic transmission and neural development, but it is unclear how pH is involved in AMPAR trafficking. We show that the proton-activated chloride (PAC) channel localizes to early and recycling endosomes in neurons and prevents endosome hyper-acidification. Loss of PAC reduces AMPAR endocytosis during chemical LTD in primary neurons, while basal trafficking and LTP are unaffected. Pyramidal neuron-specific PAC knockout mice have impaired hippocampal LTD, but not LTP, and perform poorly in the Morris water maze reversal test, exhibiting impaired behavioral adaptation. We conclude that proper maintenance of endosomal pH by PAC in neurons is important during LTD to regulate AMPAR trafficking in a manner critical for animal physiology and behavior.

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• Dissociation of SYNGAP1 enzymatic and structural roles: Intrinsic excitability and seizure susceptibility

  Proceedings of the National Academy of Sciences · 2025-04-28 · 11 citations

  articleOpen accessSenior authorCorresponding

  SYNGAP1 is a key Ras-GAP protein enriched at excitatory synapses, with mutations causing intellectual disability and epilepsy in humans. Recent studies have revealed that in addition to its role as a negative regulator of G-protein signaling through its GAP enzymatic activity, SYNGAP1 plays an important structural role through its interaction with postsynaptic density proteins. Here, we reveal that intrinsic excitability deficits and seizure phenotypes in heterozygous Syngap1 knockout (KO) mice are differentially dependent on Syngap1 GAP activity. Cortical excitatory neurons in heterozygous KO mice displayed reduced intrinsic excitability, including lower input resistance, and increased rheobase, a phenotype recapitulated in GAP-deficient Syngap1 mutants. However, seizure severity and susceptibility to pentylenetetrazol (PTZ)-induced seizures were significantly elevated in heterozygous KO mice but unaffected in GAP-deficient mutants, implicating the structural rather than enzymatic role of Syngap1 in seizure regulation. These findings highlight the complex interplay between SYNGAP1 structural and catalytic functions in neuronal physiology and disease.

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• The ionotropic AMPA receptor contributes to autoimmunity via altered regulatory T cell differentiation

  iScience · 2025-11-28

  articleOpen access

  studies reveal that the deletion of the AMPAR intrinsically promotes Treg generation. Mechanistically, AMPAR deletion increases IL2 signaling and activates the mTORC1 pathway, supporting Treg development and function. These novel findings suggest that a function of the AMPAR in CD4 T cells is to limit immune suppression by restricting Treg differentiation. Targeting AMPARs on T cells could offer a novel therapeutic approach for the treatment of autoimmune disease.

  PublisherDOI

• Dissociation of SYNGAP1 Enzymatic and Structural Roles: Intrinsic Excitability and Seizure Susceptibility

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-14 · 1 citations

  preprintOpen accessSenior authorCorresponding

  SYNGAP1 is a key Ras-GAP protein enriched at excitatory synapses, with mutations causing intellectual disability and epilepsy in humans. Recent studies have revealed that in addition to its role as a negative regulator of G-protein signaling through its GAP enzymatic activity, SYNGAP1 plays an important structural role through its interaction with post-synaptic density proteins. Here, we reveal that intrinsic excitability deficits and seizure phenotypes in heterozygous Syngap1 knockout (KO) mice are differentially dependent on Syngap1 GAP activity. Cortical excitatory neurons in heterozygous KO mice displayed reduced intrinsic excitability, including lower input resistance, and increased rheobase, a phenotype recapitulated in GAP-deficient Syngap1 mutants. However, seizure severity and susceptibility to pentylenetetrazol (PTZ)-induced seizures were significantly elevated in heterozygous KO mice but unaffected in GAP-deficient mutants, implicating the structural rather than enzymatic role of Syngap1 in seizure regulation. These findings highlight the complex interplay between SYNGAP1 structural and catalytic functions in neuronal physiology and disease. Significance Statement Mutations in the SYNGAP1 gene are a major cause of intellectual disability, autism, and epilepsy. The SYNGAP1 protein is an important constituent of postsynaptic specializations, and two distinct functions have been characterized: a structural function, carried by its C-terminal PDZ domain, that organizes the composition of the postsynaptic density, and an enzymatic function, in which its GAP domain negatively regulates small GTPases. So far, no electrophysiological/behavioral phenotype of SYNGAP1 has been directly linked to the GAP catalytic activity. Here, we describe that while the GAP catalytic activity does not contribute to the increased seizure susceptibility seen in SYNGAP1 haploin-sufficiency, it does regulate the intrinsic excitability of upper lamina pyramidal cells.

  PublisherDOI

• Sex and experience dependent regulation of synaptic protein turnover

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-25 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Synaptic transmission can be carefully tuned through plasticity mechanisms that regulate synaptic strength, structure, and number. In vivo measurements demonstrate remarkable spine dynamics, with subsets of synapses persisting for months. This correlates with the extreme longevity of certain memories, which can persist for an organism's lifetime. The molecular basis supporting the long-term stability of specific synapses and the long-term durability of memories remains unknown. At the protein level, most proteins persist for a relatively short amount of time before they are degraded and replaced with new molecules. However, recent work has identified a population of proteins, including those present at the synapse, that are exceptionally long-lived. It has been speculated that long-lived proteins (LLPs) could contribute to long-term synapse stability, function, and memory. Here, we used stable isotope labeling in mammals (SILAM) to first identify LLPs in the post synaptic density (PSD) of the hippocampus and subsequently determine if protein turnover rates varied by sex or following learning. We identified novel synaptic LLPs and found that both sex and experience can regulate synaptic protein turnover rates. We identified sex-dependent changes in protein turnover rates in autism spectrum disorder (ASD) risk genes, including increased stability of Gabrg2, a GABA-A receptor subunit, in male mice. Furthermore, we observed stabilization of a subset of PSD proteins, such as Shank3, following contextual fear conditioning. We propose that sex and experience dependent changes in protein turnover rates could help explain sex-differences in psychiatric risk and aid our understanding of the molecular mechanisms that support learning and memory.

  PublisherDOI

• Transcriptional signatures of hippocampal tau pathology in primary age-related tauopathy and Alzheimer’s disease

  Cell Reports · 2025-03-01 · 11 citations

  articleOpen access

  In primary age-related tauopathy (PART) and Alzheimer's disease (AD), tau aggregates share a similar structure and anatomic distribution, which is distinct from tau pathology in other diseases. However, transcriptional similarities between PART and AD and gene expression changes within tau-pathology-bearing neurons are largely unknown. Using GeoMx spatial transcriptomics, mRNA was quantified in hippocampal neurons with and without tau pathology in PART and AD. Synaptic genes were down-regulated in disease overall but up-regulated in tau-pathology-positive neurons. Two transcriptional signatures were associated with intraneuronal tau, both validated in a cortical AD dataset. Genes in the up-regulated signature were enriched in calcium regulation and synaptic function. Notably, transcriptional changes associated with intraneuronal tau in PART and AD were similar, suggesting a possible mechanistic relationship. These findings highlight the power of molecular analysis stratified by pathology and provide insight into common pathways associated with tau pathology in PART and AD.

  PublisherDOI

• Architecture, Activation, and Conformational Plasticity in the GluA4 AMPA Receptor

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-16 · 2 citations

  preprintOpen access

  AMPA-subtype glutamate receptors (AMPARs), composed of subunits GluA1-4, mediate fast, excitatory synaptic transmission in the brain. After glutamate binding, AMPAR ion channels exhibit multiple subconductance states that tune neuronal responses to glutamate. GluA4 is the rarest subunit in the brain but is enriched in interneurons. Rising evidence points to the role of GluA4 AMPARs in the development of neurological diseases, but the structural mechanisms of GluA4 function have remained enigmatic. Here, from bilayer recordings and cryo-electron microscopy (cryo-EM), we report the unique features of GluA4 AMPARs that tune receptor function. We find that GluA4 AMPARs have a canonical "Y" shaped architecture where local dimer pairs are domain-swapped between the amino terminal domain (ATD) and ligand binding domain (LBD), both of which comprise the extracellular domain. All four LBDs are glutamate bound yet open the GluA4 ion channel by asymmetric hinging in all channel helices. We observe that the glutamate-saturated LBD has conformational plasticity, and the different conformations of the LBD tune the ion channel gate below. These data provide a framework for understanding how channel subconductance can occur during conditions of saturating glutamate, outline the unique properties of GluA4, expand our understanding of conformational plasticity in AMPARs, and will inform therapeutic design.

  PublisherDOI

• A compendium of human gene functions derived from evolutionary modelling

  Nature · 2025-02-26 · 31 citations

  articleOpen access

  Abstract A comprehensive, computable representation of the functional repertoire of all macromolecules encoded within the human genome is a foundational resource for biology and biomedical research. The Gene Ontology Consortium has been working towards this goal by generating a structured body of information about gene functions, which now includes experimental findings reported in more than 175,000 publications for human genes and genes in experimentally tractable model organisms 1,2 . Here, we describe the results of a large, international effort to integrate all of these findings to create a representation of human gene functions that is as complete and accurate as possible. Specifically, we apply an expert-curated, explicit evolutionary modelling approach to all human protein-coding genes. This approach integrates available experimental information across families of related genes into models that reconstruct the gain and loss of functional characteristics over evolutionary time. The models and the resulting set of 68,667 integrated gene functions cover approximately 82% of human protein-coding genes. The functional repertoire reveals a marked preponderance of molecular regulatory functions, and the models provide insights into the evolutionary origins of human gene functions. We show that our set of descriptions of functions can improve the widely used genomic technique of Gene Ontology enrichment analysis. The experimental evidence for each functional characteristic is recorded, thereby enabling the scientific community to help review and improve the resource, which we have made publicly available.

  PublisherOA PDFDOI

Recent grants

• NIH Grant P50MH084020

  NIH · $9.2M · 2013

• NIH Grant P50MH068830

  NIH · $17.3M · 2008

• Longitudinal in vivo imaging of synaptic pathologies of Alzheimer's disease

  NIH · $450k · 2020–2022

• JHU Center for Neuroscience Research

  NIH · $21.8M · 2005–2021

• Multiplex in vivo imaging of cell-specific and circuit-specific signaling pathways during synaptic plasticity

  NIH · $1.8M · 2016–2020

Frequent coauthors

• Kogo Takamiya

  University of Miyazaki

  175 shared

• Richard C. Johnson

  Discovery Institute

  127 shared

• Ingie Hong

  Johns Hopkins University

  111 shared

• Yoichi Araki

  107 shared

• Paul F. Worley

  Johns Hopkins Medicine

  98 shared

• Gavin Rumbaugh

  Scripps Research Institute

  96 shared

• Craig Blackstone

  National Institute of Neurological Disorders and Stroke

  87 shared

• Alexei M. Bygrave

  Johns Hopkins University

  77 shared

Education

• Ph.D., Biochemistry, Molecular and Cell Biology

  Cornell University

  1982

• A.B., Biochemistry

  Vassar College

  1975