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

This review (2017) examines synaptic deficits associated with chronic stress and persisting symptoms of PTSD and characterizes the rapid efficacy of ketamine via mechanisms that open up a window of increased neuroplasticity and enable cognitive and behavioral therapies to treat patients more effectively.

Abstract

“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.

Summary: Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.”

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

Summary

Stress reduces the number of synapses and causes neural atrophy in the medial prefrontal cortex of rats. This is because repeated stress decreases the signaling of the BDNF-TrkB and mTORC1 pathways, which are essential for regulation of synaptic plasticity.

A review of the neurobiology and treatment of PTSD highlights the potential clinical importance of stress-related loss of synaptic connectivity.

Fig. 3 illustrates how neuroinflammation, HPA activation, and stress-related alterations in circuit function interact to contribute to synaptic loss.

Fig. 4 shows that layer V pyramidal neurons had fewer dendritic spines after 21 days of chronic uncontrollable stress than after a single dose of ketamine.

Ketamine causes a burst of glutamate via disinhibition of GABA interneurons, which stimulates AMPA receptors, which causes depolarization and activation of voltage-dependent Ca2+ channels, which leads to release of BDNF and increased mTORC1 signaling, which leads to increased synthesis of proteins required for synapse maturation and formation.

The authors acknowledge the support of the US Department of Veterans Affairs, the US Department of Defense, the National Center for Advancing Translational Science, the State of Connecticut, and the Abraham Ribicoff Research Facilities of the Connecticut Mental Health Center.

Compliance with Ethical Standards

Dr. Gerard Sanacora has received consultancy fees from Allergan, Alkermes, BioHaven Pharmaceuticals Holding Company, Janssen, Merck, Sage, Taisho Pharmaceuticals, Takeda, and Vistagen Therapeutics.

• Of importance

A psychobiology of posttraumatic stress disorder is proposed, which includes abnormal fear memory as a model for posttraumatic stress disorder, and the extinction of conditioned fear in rodents, humans, and anxiety disorders. The contextual brain, synaptic plasticity and the amygdala are important in fear conditioning, extinction and psychopathology. Context processing is also important for the treatment of post-traumatic stress disorder. Exposure therapy is a gold standard for PTSD treatment and can be enhanced by the use of medications. Propranolol is a medication that can be used to enhance the effects of psychotherapy by increasing neuroplasticity.

A systematic meta-analysis of cognitive impairments associated with posttraumatic stress disorder. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. A paper that highlights the role of synaptic plasticity in stress, depression, and antidepressant therapeutic effects. Post-traumatic stress disorder (PTSD) is characterized by dysregulation of glucocorticoids, immune mediators of stress susceptibility, and neuroendocrine activity. Urinary free-cortisol levels are remarkably variable in subgroups of combat veterans with PTSD during an intensive exposure treatment program. Inslicht SS, Marmar CR, Neylan TC, Metzler TJ, Hart SL, Otte C, et al. found that women with intimate partner violence-related posttraumatic stress disorder had increased cortisol levels.

et al. Decreased SGK1 expression and function contributes to behavioral deficits induced by traumatic stress, and high dose hydrocortisone immediately after trauma may alter the trajectory of PTSD. Passos IC, Vasconcelos-Moreno MP, Costa LG, Kunz M, Brietzke E, Quevedo J, et al. found that inflammatory markers are associated with post-traumatic stress disorder. A systematic review and meta-analysis of magnetic resonance imaging measurements of structural volumes in posttraumatic stress disorder was performed by O’Doherty DC, Chitty KM, Saddiqui S, Bennett MR, Lagopoulos J, et al. Posttraumatic stress disorder (PTSD) is associated with reduced hippocampal volume and connectivity with the ventromedial prefrontal cortex in military veterans, and with altered default mode network (DMN) resting state functional connectivity following a mindfulness-based exposure therapy for PTSD in combat veterans of Afghanistan and Iraq.

A study found that veterans with posttraumatic stress disorder and traumatic brain injury have abnormalities in the insula subregion resting-state functional connectivity with amygdala complexes, and that these abnormalities may be related to the interplay of PTSD and TBI effects on brain imaging. Veterans with mild traumatic brain injury, post-traumatic stress disorder, and combined mild traumatic brain injury/post-traumatic stress disorder have lower resilience than non-veterans. The brain changes in patients with posttraumatic stress disorder and associated alcoholism are studied using MRI, and the results indicate that the hippocampus is vulnerable and plasticity of the prefrontal cortex over the life course.

Stress alters spatial representation and bursting patterns of place cells in behaving mice. Chronic stress enhances ibotenic acid-induced damage selectively within the CA3 region of the hippocampal brain in male rats. A computational analysis of chronic stress on intrinsic and synaptic excitability in the hippocampus suggests that chronic stress can lead to depression-like behavior. Moreover, exercise can alter the cytoarchitecture of the adult dentate gyrus by increasing cellular proliferation, dendritic complexity, and spine density. Exercise promotes experience-induced brain plasticity, enhances hippocampal neurogenesis and synaptic plasticity, and prevents the development of depressive behaviors in rats administered corticosterone, and reduces white matter connectivity disturbances in veterans with posttraumatic stress disorder.

A classic long-term follow-up of posttraumatic stress disorder in Vietnam Era veterans, the National Vietnam Veterans Longitudinal Study provides evidence that brain plasticity-based therapeutics may be effective in treating PTSD. Stress, glucocorticoids, and glutamate transmission in the brain are linked, and inflammation, glutamate, and glia are a trio of trouble in mood disorders. The authors of this article reviewed the research on the role of neurotrophic factors in the etiology and treatment of post-traumatic stress disorder and found that the study of women with childhood sexual abuse and posttraumatic stress disorder showed deficits in hippocampal structure and function. 107. Fluoxetine prevents the development of depressive-like behavior in a mouse model of cancer related fatigue.

108 studies have shown that antidepressants reduce neuroinflammatory responses and astroglial alpha-synuclein accumulation in a transgenic mouse model of multiple system atrophy, and 109 studies have shown that NMDA receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Ketamine treatment and global brain connectivity in major depression, reduced global functional connectivity of the medial prefrontal cortex in major depressive disorder, NMDA receptor inhibition-independent antidepressant actions of ketamine metabolites, and the role of adipokines in the rapid antidepressant effects of ketamine. Ketamine’s antidepressant-like effect is mediated by inhibition of nitrergic Rheb degradation and mTOR signaling, and involves modulation of GABAA and GABAB receptors. Scopolamine increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. Ketamine might promote fear extinction via mTORC1 signaling. 126 papers have shown that AMPA receptor potentiators can be used to treat depression, 127 papers have shown that scopolamine can be used to treat depression, and 129 papers have shown that neuroplasticity can be used to treat anxiety and mood disorders.