Stephen Rayport, MD, PhD
Stephen Rayport is a Professor of Neurobiology in Psychiatry, in the Division of Molecular Therapeutics at the Columbia University Irving Medical Center. He did undergraduate work at Harvard, where he studied the evolution of vision with George Wald. He did MD-PhD training at Columbia where he studied the development of synaptic learning mechanisms with Eric Kandel. He trained in Psychiatry at Columbia and the NYS Psychiatric Institute. His program of laboratory research focuses on dopamine and glutamate synaptic transmission relevant to schizophrenia and addiction.
- Professor of Neurobiology (in Psychiatry) at CUMC
- Chair, NYSPI Institutional Animal Care and Use Committee
Research focus is on cellular mechanisms of synaptic function and drug action in brain circuits relevant to addiction and schizophrenia. Using conditional and intersectional strategies we have identified behavioral roles of dopamine neuron glutamate cotransmission, in modulation of salience learning and amphetamine responsiveness. Motivated by the discovery of the reduction in glutamate cotransmission following acute amphetamine, and the diminished amphetamine responsiveness of mice with reduced glutamate cotransmission, we sought to identify the most susceptible dopamine neuron connections. We have now mapped dopamine neuron synaptic connectivity across the striatum, revealing a synaptic landscape of fast dopamine, glutamate and GABA signaling, including a novel mode of dopamine neuron glutamate cotransmission engaging metabotropic glutamate receptors. Now, we are elaborating amphetamine effects on the synaptic map, in response to both acute and chronic amphetamine, and how this translates into altered patterns of striatal activity. In efforts to extrapolate the mapping approach to clinical application, we have developed a novel proximity based methodology for synaptic visualization in transgenic mice, which we have extended to non-transgenic tissue from non-human primates, with potential for further extension to post-mortem human striatal tissue. We have targeted glutaminase (Gls1) for studies of dopamine neuron glutamate transmission as well as more broadly to define glutamatergic circuits crucial in the pathogenesis of schizophrenia and addiction. We have found that Gls1-deficient mice exhibit phenotypes consistent with schizophrenia resilience. In complimentary studies, we have targeted glutamate dehydrogenase (Glud1), and shown that CNS-Glud1 knockout mice have deficits in schizophrenia symptom domains, as well as a hippocampal imaging phenotype of hyperactivity, increased glutamate content, and associated atrophy. We are dissecting the regional basis for the phenotype and testing the therapeutic potential of glutaminase inhibition for the treatment of schizophrenia.
Significant contributions include:
- Eestablishing the first postnatal cell cultures of identified dopamine neurons.
- Elucidating a vesicular mechanism of amphetamine action.
- Identifying glutamate as a fast dopamine neuron transmitter.
- Generation and characterization of Gls1-deficient mice.
- Characterizing the schizophrenia resilience phenotype of Gls1-heterozygous mice.
- Showing that the phenotype is based significantly on reduction of dopamine neuron glutamate synaptic transmission.
- Characterizing the schizophrenia phenotype of glutamate dehydrogenase (Glud1) deficient mice.
- Developing genetic pharmacotherapy as a drug-development strategy for validating the potential of drug targets in advance of the development of drugs.
- Mapping dopamine neuron synaptic transmission across the striatum.
- Models of Psychiatric Disorders
- Systems and Circuits
- Chuhma N, Oh SJ, Rayport S. The dopamine neuron synaptic map in the striatum. SSRN Electronic Journal. 2022:4207573.
- Ztaou S, Oh SJ, Tepler S, Fleury S, Matamales M, Bertran-Gonzalez J, Chuhma N, Rayport S. Single dose of amphetamine induces delayed subregional attenuation of cholinergic interneuron activity in the striatum. eNeuro. 2021;8(5):0196-21.2021.
- Eskenazi D, Malave L, Mingote S, Yetnikoff L, Ztaou S, Velicu V, Rayport S, Chuhma N. Dopamine neurons that cotransmit glutamate, from synapses to circuits to behavior. Front Neural Circuits. 2021;15:665386.
- Eskenazi D, Chuhma N, Mingote S, Ztaou S, Rayport S. Functional connectome mapping. In: Wilson G, Michael A, editors. Compendium of In-Vivo monitoring in Real-Time Molecular Neuroscience. Singapore: World Scientific Publishing Company; 2020. p. 49-71.
- Mingote S, Amsellem A, Kempf A, Rayport S, Chuhma N. Dopamine-glutamate neuron projections to the nucleus accumbens medial shell and behavioral switching. Neurochem Int. 2019;129:104482.
- Lander SS, Khan U, Lewandowski N, Chakraborty D, Provenzano FA, Mingote S, Chornyy S, Frigerio F, Maechler P, Kaphzan H, Small SA, Rayport S, Gaisler-Salomon I. Glutamate dehydrogenase-deficient mice display schizophrenia-like behavioral abnormalities and CA1-specific hippocampal dysfunction. Schizophr Bull. 2019;45(1):127-37.
- Kosten L, Chowdhury GMI, Mingote S, Staelens S, Rothman DL, Behar KL, Rayport S. Glutaminase activity in GLS1 Het mouse brain compared to putative pharmacological inhibition by ebselen using ex vivo MRS. Neurochem Int. 2019;129:104508.
- Chuhma N, Mingote S, Yetnikoff L, Kalmbach A, Ma T, Ztaou S, Sienna AC, Tepler S, Poulin JF, Ansorge M, Awatramani R, Kang UJ, Rayport S. Dopamine neuron glutamate cotransmission evokes a delayed excitation in lateral dorsal striatal cholinergic interneurons. eLIFE. 2018;7:e39786.
- Mingote S, Chuhma N, Kalmbach A, Thomsen GM, Wang Y, Mihali A, Sferrazza C, Zucker-Scharff I, Siena AC, Welch MG, Lizardi-Ortiz J, Sulzer D, Moore H, Gaisler-Salomon I, Rayport S. Dopamine neuron dependent behaviors mediated by glutamate cotransmission. eLIFE. 2017;6:e27566.
- Aguilar JI, Dunn M, Mingote S, Karam CS, Farino ZJ, Sonders MS, Choi SJ, Grygoruk A, Zhang Y, Cela C, Choi BJ, Flores J, Freyberg RJ, McCabe BD, Mosharov EV, Krantz DE, Javitch JA, Sulzer D, Sames D, Rayport S, Freyberg Z. Neuronal depolarization drives increased dopamine synaptic vesicle loading via VGLUT. Neuron. 2017;95(5):1074-88.
- Mingote S, Masson J, Gellman C, Thomsen GM, Lin C-S, Merker RJ, Gaisler-Salomon I, Wang Y, Ernst R, Hen R, Rayport S. Genetic pharmacotherapy as an early CNS drug development strategy: Testing glutaminase inhibition for schizophrenia treatment in adult mice. Front Syst Neurosci. 2016;9:165.
- Mingote S, Chuhma N, Kusnoor SV, Field B, Deutch AY, Rayport S. Functional connectome analysis of dopamine neuron glutamatergic connections in forebrain regions. J Neurosci. 2015;35(49):16259-71.
- Chuhma N, Mingote S, Moore H, Rayport S. Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling. Neuron. 2014;81(4):901-12.
- Gaisler-Salomon I, Miller GM, Chuhma N, Lee S, Zhang H, Ghoddoussi F, Lewandowski N, Fairhurst S, Wang Y, Conjard-Duplany A, Masson J, Balsam P, Hen R, Arancio O, Galloway MP, Moore HM, Small SA, Rayport S. Glutaminase-deficient mice display hippocampal hypoactivity, insensitivity to pro-psychotic drugs and potentiated latent inhibition: relevance to schizophrenia. Neuropsychopharmacology. 2009;34(10):2305-22.