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Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression

Nature Neuroscience volume 16, pages 464–472 (2013)Cite this article

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Abstract

The causes of major depression remain unknown. Antidepressants elevate concentrations of monoamines, particularly serotonin, but it remains uncertain which downstream events are critical to their therapeutic effects. We found that endogenous serotonin selectively potentiated excitatory synapses formed by the temporoammonic pathway with CA1 pyramidal cells via activation of serotonin receptors (5-HT1BRs), without affecting nearby Schaffer collateral synapses. This potentiation was expressed postsynaptically by AMPA-type glutamate receptors and required calmodulin-dependent protein kinase–mediated phosphorylation of GluA1 subunits. Because they share common expression mechanisms, long-term potentiation and serotonin-induced potentiation occluded each other. Long-term consolidation of spatial learning, a function of temporoammonic-CA1 synapses, was enhanced by 5-HT1BR antagonists. Serotonin-induced potentiation was quantitatively and qualitatively altered in a rat model of depression, restored by chronic antidepressants, and required for the ability of chronic antidepressants to reverse stress-induced anhedonia. Changes in serotonin-mediated potentiation, and its recovery by antidepressants, implicate excitatory synapses as a locus of plasticity in depression.

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Figure 1: 5-HT1BR activation selectively potentiates TA-CA1 cell excitatory synapses.
Figure 2: Expression of 5-HT1BR–induced potentiation of TA-CA1 synapses is mediated postsynaptically.
Figure 3: Anpirtoline activates CaMK and increases phosphorylation of GluA1 at serine 831 in SLM tissue.
Figure 4: 5-HT1BR–mediated potentiation occludes LTP at TA-CA1 synapses and influences memory consolidation.
Figure 5: Spatial memory consolidation is affected by endogenous activation of 5-HT1BRs.
Figure 6: Chronic stress enhances, whereas chronic antidepressants eliminate, the effect of anpirtoline on TA-CA1 synaptic transmission.
Figure 7: 5-HT1BR–dependent potentiation of GluA1 receptors is necessary for the therapeutic action of antidepressants.

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Acknowledgements

We thank S. Ahmari and R. Hen (Columbia University) for providing Hrt1b−/− mice, B. Alger, T. Blanpied, T. Gould, J. Kim and M. McCarthy for their comments, S. Aungst for advice on immunohistochemistry, and H. Zimmerman, L. Mok and M. Taylor for technical assistance. This work was funded by a Mr. and Mrs. Robert and Lee Peterson Southwest Florida National Alliance for Research on Schizophrenia and Depression Young Investigator Award (X.C.), the Howard Hughes Medical Institute (R.L.H.) and the US National Institutes of Health (R.L.H., H.-K.L., X.C. and S.M.T.).

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Author notes

  1. Xiang Cai

    Present address: Present address: Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA.,

  2. Xiang Cai and Angy J Kallarackal: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Xiang Cai, Angy J Kallarackal, Mark D Kvarta & Scott M Thompson

  2. Programs in Neuroscience and Membrane Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Angy J Kallarackal, Mark D Kvarta & Scott M Thompson

  3. Medical Scientist Training Program, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Mark D Kvarta

  4. Department of Psychology, Saint Mary's College of Maryland, St. Mary's City, Maryland, USA

    Sasha Goluskin, Kaitlin Gaylor & Aileen M Bailey

  5. The Zanvyl Krieger Mind/Brain Institute, Johns Hopkins University, Baltimore, Maryland, USA

    Hey-Kyoung Lee

  6. Solomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Richard L Huganir

  7. Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA

    Scott M Thompson

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Contributions

X.C., A.J.K., M.D.K., A.M.B. and S.M.T. designed the study. X.C., A.J.K., M.D.K., S.G., K.G. and A.M.B. performed the experiments and analyzed the data. H.-K.L. and R.L.H. provided the GluA1 S831A mice. X.C., A.J.K. and S.M.T. prepared the manuscript. All of the authors discussed the results and commented on the manuscript.

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Correspondence to Scott M Thompson.

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Cai, X., Kallarackal, A., Kvarta, M. et al. Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression. Nat Neurosci 16, 464–472 (2013). https://doi.org/10.1038/nn.3355

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