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Lower synaptic density is associated with depression severity and network alterations

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  • Sophie E. Holmes

    (Yale School of Medicine)

  • Dustin Scheinost

    (Radiology and Biomedical Imaging, Yale School of Medicine)

  • Sjoerd J. Finnema

    (Yale School of Medicine)

  • Mika Naganawa

    (Radiology and Biomedical Imaging, Yale School of Medicine)

  • Margaret T. Davis

    (Yale School of Medicine)

  • Nicole DellaGioia

    (Yale School of Medicine)

  • Nabeel Nabulsi

    (Radiology and Biomedical Imaging, Yale School of Medicine)

  • David Matuskey

    (Yale School of Medicine
    Radiology and Biomedical Imaging, Yale School of Medicine)

  • Gustavo A. Angarita

    (Yale School of Medicine)

  • Robert H. Pietrzak

    (Yale School of Medicine
    U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System)

  • Ronald S. Duman

    (Yale School of Medicine)

  • Gerard Sanacora

    (Yale School of Medicine)

  • John H. Krystal

    (Yale School of Medicine
    U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System)

  • Richard E. Carson

    (Radiology and Biomedical Imaging, Yale School of Medicine)

  • Irina Esterlis

    (Yale School of Medicine
    U.S. Department of Veteran Affairs National Center for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System)

Abstract

Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand [11C]UCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.

Suggested Citation

  • Sophie E. Holmes & Dustin Scheinost & Sjoerd J. Finnema & Mika Naganawa & Margaret T. Davis & Nicole DellaGioia & Nabeel Nabulsi & David Matuskey & Gustavo A. Angarita & Robert H. Pietrzak & Ronald S., 2019. "Lower synaptic density is associated with depression severity and network alterations," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09562-7
    DOI: 10.1038/s41467-019-09562-7
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    Cited by:

    1. Haven Tillmon & Breeanne M. Soteros & Liang Shen & Qifei Cong & Mackenna Wollet & Julianne General & Hanna Chin & John Beichen Lee & Flavia R. Carreno & David A. Morilak & Jun Hee Kim & Gek Ming Sia, 2024. "Complement and microglia activation mediate stress-induced synapse loss in layer 2/3 of the medial prefrontal cortex in male mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Justine Y. Hansen & Golia Shafiei & Jacob W. Vogel & Kelly Smart & Carrie E. Bearden & Martine Hoogman & Barbara Franke & Daan Rooij & Jan Buitelaar & Carrie R. McDonald & Sanjay M. Sisodiya & Lianne , 2022. "Local molecular and global connectomic contributions to cross-disorder cortical abnormalities," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. David J. Whiteside & Negin Holland & Kamen A. Tsvetanov & Elijah Mak & Maura Malpetti & George Savulich & P. Simon Jones & Michelle Naessens & Matthew A. Rouse & Tim D. Fryer & Young T. Hong & Frankli, 2023. "Synaptic density affects clinical severity via network dysfunction in syndromes associated with frontotemporal lobar degeneration," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Golia Shafiei & Ben D. Fulcher & Bradley Voytek & Theodore D. Satterthwaite & Sylvain Baillet & Bratislav Misic, 2023. "Neurophysiological signatures of cortical micro-architecture," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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