A Two-Hit Model of The Biological Origin of Posttraumatic Stress Disorder (PTSD)

Posttraumatic stress disorder (PTSD) is a debilitating disorder that can develop following exposure to a traumatic event. Although the cause of PTSD is known, the brain mechanisms of its development remain unknown, especially why it arises in some people but not in others. Most of the research on PTSD has dealt with psychological and brain mechanisms underlying its symptomatology, including intrusive memories, fear and avoidance (see ref.1 for a broad coverage of PTSD research)(1). Here we focus, instead, on the origin of PTSD, namely on the neural mechanisms underlying its development. Specifically, we propose a two-hit model for PTSD development, with the following components. (a) The 1st hit is a neuroimmune challenge, as a preexisting condition, and the 2nd hit is intense glutamatergic neurotransmission, induced by the traumatic event; (b) the key molecule that mediates the effects of these two hits is intercellular adhesion molecule 5 (ICAM-5) which was found to be differentially expressed in PTSD(2). ICAM-5 is activated by neuroimmune challenge(3,4) and glutamatergic neurotransmission(5,6), it further enhances glutamatergic transmission(6), and exerts a potent effect on synapse formation and neural plasticity, in addition to immunoregulatory functions(3,4,7); and (c) with respect to the neural network(s) involved, the brain areas most involved are medial temporal cortical areas, and interconnected cortical and subcortical areas(8–10). We hypothesize that the net result of intense glutamatergic transmission in those areas induced by a traumatic event in the presence of ongoing neuroimmune challenge leads to increased levels of ICAM-5 which further enhances glutamatergic transmission and thus leads to a state of a neural network with highly correlated neural interactions, as has been observed in functional neuroimaging studies(8–10). We assume that such a “locked-in” network underlies the intrusive re-experiencing in PTSD and maintains associated symptomatology, such as fear and avoidance.