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Relevance of interactions between dopamine and glutamate neurotransmission in schizophrenia

Molecular Psychiatry volume 27, pages 3583–3591 (2022)Cite this article

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Abstract

Dopamine (DA) and glutamate neurotransmission are strongly implicated in schizophrenia pathophysiology. While most studies focus on contributions of neurons that release only DA or glutamate, neither DA nor glutamate models alone recapitulate the full spectrum of schizophrenia pathophysiology. Similarly, therapeutic strategies limited to either system cannot effectively treat all three major symptom domains of schizophrenia: positive, negative, and cognitive symptoms. Increasing evidence suggests extensive interactions between the DA and glutamate systems and more effective treatments may therefore require the targeting of both DA and glutamate signaling. This offers the possibility that disrupting DA-glutamate circuitry between these two systems, particularly in the striatum and forebrain, culminate in schizophrenia pathophysiology. Yet, the mechanisms behind these interactions and their contributions to schizophrenia remain unclear. In addition to circuit- or system-level interactions between neurons that solely release either DA or glutamate, here we posit that functional alterations involving a subpopulation of neurons that co-release both DA and glutamate provide a novel point of integration between DA and glutamate systems, offering a key missing link in our understanding of schizophrenia pathophysiology. Better understanding of mechanisms underlying DA/glutamate co-release from these neurons may therefore shed new light on schizophrenia pathophysiology and lead to more effective therapeutics.

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Fig. 1: Interplay between dopamine and glutamate systems is disrupted in schizophrenia.
Fig. 2: Model for vesicular glutamate transporter 2 (VGLUT2)-mediated role in elevated striatal dopaminergic neurotransmission in schizophrenia.

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Acknowledgements

All figures were created with BioRender.com.

Funding

This work is supported by the National Institutes of Health F31NS118811 (SAB), R21AG068607 (ZF), R21DA052419 (ZF and RWL), R21AA028800 (ZF and RWL), and R01DK124219 (ZF).

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Authors and Affiliations

  1. Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Silas A. Buck & M. Quincy Erickson-Oberg

  2. Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Silas A. Buck, M. Quincy Erickson-Oberg & Zachary Freyberg

  3. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, 02118, USA

    Ryan W. Logan

  4. Center for Systems Neuroscience, Boston University, Boston, MA, 02118, USA

    Ryan W. Logan

  5. Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Zachary Freyberg

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  1. Silas A. Buck
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SAB and ZF conceived the idea and designed the manuscript. SAB, MQEO, RWL, and ZF wrote the manuscript. SAB, MQEO, RWL, and ZF created figures and performed editing. All authors approved the final manuscript version.

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Correspondence to Zachary Freyberg.

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Buck, S.A., Quincy Erickson-Oberg, M., Logan, R.W. et al. Relevance of interactions between dopamine and glutamate neurotransmission in schizophrenia. Mol Psychiatry 27, 3583–3591 (2022). https://doi.org/10.1038/s41380-022-01649-w

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