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

Introduction

Research on post-traumatic stress disorder (PTSD) has made substantial progress within a translational neuroscience framework, most notably in understanding fear regulation. PTSD is characterised by biased threat appraisal, overgeneralised fear, impaired fear extinction and altered contextual threat processing, which are believed to underlie symptoms such as hypervigilance, intrusive re-experiencing, and avoidance. Despite these advances, important gaps remain: in particular, it is unclear why trauma-related fear memories are often resistant to extinction and whether persistent symptoms reflect underlying deficits in neuroplasticity with a structural substrate. Krystal and colleagues set out to draw attention to an often-neglected consequence of stress models that may be relevant to PTSD: stress-related loss of synaptic connectivity. The review synthesises preclinical and emerging clinical evidence and considers the hypothesis that PTSD may be a ‘‘synaptic disconnection syndrome’’, with implications for novel therapeutics—most notably ketamine, which the authors propose might act, at least in part, by restoring synaptic connectivity and thereby producing rapid clinical benefits.