Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

Krystal, John H.; Abdallah, Chadi G.; Averill, Lynette A.; Kelmendi, Benjamin; Harpaz‐Rotem, Ilan; Sanacora, Gerard; Southwick, Steven M.; Duman, Ronald S.

doi:10.1007/s11920-017-0829-z

Cited by 95 publications

(65 citation statements)

References 131 publications

(132 reference statements)

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“…Importantly, the vmPFC, particularly the infralimbic PFC in rodents, as discussed previously, is required for fear extinction. We have reported that the rapid antidepressant ketamine enhances the extinction of fear in rats [98] consistent with recent clinical findings that ketamine improves PTSD symptoms in patients [99, 100]. We also found that increased fear extinction was associated with enhanced mTORC1 (mechanistic target of rapamycin complex 1) signaling in the vmPFC and that pretreatment with an inhibitor of mTORC1 blocked ketamine enhancement of extinction.…”

Section: Animal Models Of Ptsdsupporting

confidence: 88%

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Girgenti

Hare

Ghosal

et al. 2017

Curr Psychiatry Rep

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Purpose of Review Posttraumatic stress disorder (PTSD) is characterized by hyperarousal and recurrent stressful memories after an emotionally traumatic event. Extensive research has been conducted to identify the neurobiological determinants that underlie the pathophysiology of PTSD. In this review, we examine evidence regarding the molecular and cellular pathophysiology of PTSD focusing on two primary brain regions: the vmPFC and the amygdala. Recent Findings This discussion includes a review of the molecular alterations related to PTSD, focusing mainly on changes to glucocorticoid receptor signaling. We also examine postmortem gene expression studies that have been conducted to date and the molecular changes that have been observed in peripheral blood studies of PTSD patients. Causal, mechanistic evidence is difficult to obtain in human studies, so we also review preclinical models of PTSD. Summary Integration of peripheral blood and postmortem studies with preclinical models of PTSD has begun to reveal the molecular changes occurring in patients with PTSD. These findings indicate that the pathophysiology of PTSD includes disruption of glucocorticoid signaling and inflammatory systems and occurs at the level of altered gene expression. We will assess the impact of these findings on the future of PTSD molecular research.

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Section: Animal Models Of Ptsdsupporting

confidence: 88%

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Girgenti

Hare

Ghosal

et al. 2017

Curr Psychiatry Rep

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“…However, there is compelling evidence in the literature that various forms of stress destabilize the glutamate system, resulting in significant changes of glutamate release and excitatory transmission in PFC and HPC. In particular, acute inescapable stress is known to increase glutamate release/transmission in PFC, while different forms of chronic stress have been shown to reduce glutamate release/transmission in both PFC and HPC ( Musazzi et al, 2010 , 2017 ; Duman and Aghajanian, 2012 ; Yuen et al, 2012 ; Kallarackal et al, 2013 ; Marrocco et al, 2015 ; Krystal et al, 2017a ; Murrough et al, 2017 ). The functional changes in excitatory transmission are accompanied by changes in neuroarchitecture that are so far well described only for chronic stress and are starting to be unveiled for acute stress (see above).…”

Section: The Link Between Acute Stress and Psychopathologymentioning

confidence: 99%

What Acute Stress Protocols Can Tell Us About PTSD and Stress-Related Neuropsychiatric Disorders

et al. 2018

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Posttraumatic stress disorder (PTSD), the fifth most prevalent mental disorder in the United States, is a chronic, debilitating mental illness with as yet limited options for treatment. Hallmark symptoms of PTSD include intrusive memory of trauma, avoidance of reminders of the event, hyperarousal and hypervigilance, emotional numbing, and anhedonia. PTSD is often triggered by exposure to a single traumatic experience, such as a traffic accident, a natural catastrophe, or an episode of violence. This suggests that stressful events have a primary role in the pathogenesis of the disorder, although genetic background and previous life events are likely involved. However, pathophysiology of this mental disorder, as for major depression and anxiety disorders, is still poorly understood. In particular, it is unknown how can a single traumatic, stressful event induce a disease that can last for years or decades. A major shift in the conceptual framework investigating neuropsychiatric disorders has occurred in recent years, from a monoamine-oriented hypothesis (which dominated pharmacological research for over half a century) to a neuroplasticity hypothesis, which posits that structural and functional changes in brain circuitry (largely in the glutamate system) mediate psychopathology and also therapeutic action. Rodent stress models are very useful to understand pathophysiology of PTSD. Recent studies with acute or subacute stress models have shown that exposure to short-time stressors (from several minutes to a few hours) can induce not only rapid, but also sustained changes in synaptic function (glutamate release, synaptic transmission/plasticity), neuroarchitecture (dendritic morphology, synaptic spines), and behavior (cognitive functions). Some of these changes, e.g., stress-induced increased glutamate release and dendrite retraction, are likely connected and occur more rapidly than previously thought. We propose here to use a modified version of a simple and validated protocol of footshock stress to explore different trajectories in the individual response to acute stress. This new conceptual framework may enable us to identify determinants of resilient versus vulnerable response as well as new targets for treatment, in particular for rapid-acting antidepressants. It will be interesting to investigate the putative prophylactic action of ketamine toward the maladaptive effects of acute stress in this new protocol.

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“…Despite decades of psychiatric research, a comprehensive understanding of the network disruptions [1] predisposing and underlying posttraumatic stress disorder (PTSD) is still emerging [2,3]. While the majority of neuroimaging investigations have focused on structural [4] and functional [5] aspects of PTSD, there is a growing body of literature regarding white matter integrity related to the disorder.…”

Section: Introductionmentioning

confidence: 99%

Altered White Matter Diffusivity of the Cingulum Angular Bundle in Posttraumatic Stress Disorder

Averill¹,

Averill²,

Wrocklage³

et al. 2018

Complex Psychiatry

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Purpose of the Study: Prior studies showed posttraumatic stress disorder (PTSD)-related alterations in white matter integrity, but most of these studies have used region-based approaches. We address this limitation by investigating the relationship between PTSD severity and fractional anisotropy (FA) using a tract-based approach. Procedures: Structural and diffusion magnetic resonance imaging were acquired from 67 combat-exposed US Veterans and processed using FSL/FreeSurfer TRActs Constrained by UnderLying Anatomy. Partial correlations were conducted between PTSD severity and FA of the cingulum and uncinate fasciculi covarying for age, sex, and head motion. Results: Only FA of the left cingulum angular bundle (CAB) was positively correlated with PTSD symptom severity (r = 0.433, p = 0.001, df = 57) and remained significant after Bonferroni correction. Conclusions: This finding may imply greater organization of the CAB with increasing PTSD severity. The CAB connects directly to the cingulate cortex and the hippocampal subiculum, critical nodes of the default mode network, as well as being implicated in neurodegeneration pathology, decision-making, and executive functions, which may help explain previously shown alterations in this network in PTSD. Message of the Paper: Further study of white matter tract integrity in PTSD is warranted, particularly to investigate whether the CAB connections with both higher-order cognitive functioning and emotion processing regions contribute to the pathophysiology and comorbidity of PTSD.

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Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic

Cited by 95 publications

References 131 publications

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

Molecular and Cellular Effects of Traumatic Stress: Implications for PTSD

What Acute Stress Protocols Can Tell Us About PTSD and Stress-Related Neuropsychiatric Disorders

Altered White Matter Diffusivity of the Cingulum Angular Bundle in Posttraumatic Stress Disorder

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