Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic
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Purpose of review Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity.Recent findings Here, we will briefly review evidence that PTSD might be a "synaptic disconnection syndrome" and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.
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Loss of synaptic connections in mood-related circuitry is a central pathophysiological process underlying depression and other stress-related disorders, such as PTSD.
“This discovery fits with convergent evidence implicating a loss of synaptic connections in mood-related circuitry as a central pathophysiological process underlying depression and other stress-related disorders, such as PTSD 15,16 .”
From Imaging the effect of ketamine on synaptic density (SV2A) in the living brain (2022) · cites this paper as [16]
In “Toward a Synaptic Deficit Hypothesis” (page unavailable), the paper says chronic stress reduces synapses in circuits regulating mood and that synaptic loss may be an important feature of PTSD neuropathology. It presents the PTSD link as a hypothesis supported by early clinical correlates, rather than establishing synaptic loss as a central underlying process; it also does not make that broader claim for depression and other stress-related disorders. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPostmortem findings from animal models consistently demonstrate that stress induces synaptic dysfunction, including reductions in synaptic density, as measured by quantification of synaptic structure and assessments of synaptic protein expression.
“Postmortem findings from these animal models consistently demostrate that stress induces synaptic dysfunction [5,6,135], including reductions in synaptic density, as measured by both quantification of synaptic structure and assessments of synaptic protein expression”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [135]
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Lower synaptic density is associated with depression severity and network alterations
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“This discovery fits with convergent evidence implicating a loss of synaptic connections in mood-related circuitry as a central pathophysiological process underlying depression and other stress-related disorders, such as PTSD [15, 16].”
BackgroundSelf-citationPsilocybin for Trauma-Related Disorders
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Self-citation
- Authors
- Krystal, J. H., Abdallah, C. G., Averill, L. A., Kelmendi, B., Harpaz-Rotem, I., Sanacora, G., Southwick, S. M., & Duman, R. S.
- Affiliations
- Yale New Haven Hospital (US)
- Yale University (US)
- Corresponding author
- Krystal, John H.
- ORCID
- Venue
- Current Psychiatry Reports
- Published
- 2017-08-26
- Volume
- 19
- Issue
- 10
- Pages
- 74-74
- ISSN
- 1523-3812 (ISSN-L)
- 1535-1645
- PMC
- PMC5904792
- OpenAlex
- W2746761609
- Cited by
- 145
- References
- 134
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 19 · 2023: 14 · 2022: 28 · 2021: 15 · 2020: 12 · 2019: 12 · 2018: 9 · 2017: 2
- FWCI
- 1.47
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Psychiatry Reports (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Defense
- U.S. Department of Veterans Affairs
- National Center for PTSD, U.S. Department of Veterans Affairs
- National Institute on Alcohol Abuse and Alcoholism (P50AA012870)
- National Institute of Mental Health (R01MH093897)
- National Center for Research Resources (UL1RR024139)
- National Center for Advancing Translational Sciences
- Yale Center for Clinical Investigation, Yale School of Medicine
- Topics
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Keywords
- post-traumatic stress disorder, synaptic loss, ketamine, rapid-acting antidepressants, animal models of stress, PTSD pathophysiology, pharmacotherapy
- MeSH terms
- Animals, Disease Models, Animal, Humans, Ketamine, Synaptic Transmission, Neurobiology, Stress Disorders, Post-Traumatic, Excitatory Amino Acid Antagonists
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