Long term synaptic reorganization after immobilization stress: a focus on the hippocampus and the TrkB pathway

Abstract

PTSD is a trauma and stressor-related disorder that occurs after the exposure to traumatic situations. PTSD is characterized by the development of cognitive impairments such as memory dysfunction. In fact, HF, a key structure in memory formation, is one of the most affected areas in PTSD, presenting reduced volume and functional abnormalities. Despite stress effects on synaptic plasticity have been related to PTSD, long term synaptic plasticity stress-related changes remain largely unknown. The study of animal models that mimic symptoms of PTSD patients can be an effective strategy to understand the long term consequences of stress and to find novel drug targets. In this regard, several treatments have been proposed for PTSD. However, none of them has been totally successful. The BDNF/TrkB pathway has been suggested as a novel strategy since animal research has revealed an important implication of this pathway in PTSD animal models. Moreover, stress and BDNF are reciprocally modulated. Hence, it is reasonable to believe that the use of BDNF/TrkB pathway agonists, such as 7,8-dihydroxyflavone, could be an effective way to ameliorate stress effects. To address this issue we analyzed whether IMO presents similar anatomical and behavioral effects found in PTSD patients to be a putative PTSD model and the possible role of synaptic plasticity as a substrate for memory impairment. Alternatively, we investigated whether 7,8-DHF can ameliorate the PTSD-like effect of the IMO in a therapeutic window administration and whether synaptic plasticity IMO-related effects are causally related to memory impairment. IMO induced a HF volume decrease and HF-dependent task memory impairment similar to those found in others PTSD models or patients. In addition, IMO increased spine density, LTP, BDNF, HCN1 and Iba1 levels. Therefore, it is reasonable to assume that IMO-induced synaptic plasticity is involved in IMO-related memory impairment. We suggest that IMO induces a development-like process trying to compensate the detrimental effects of the initial trauma which derivate in a disconnection and posterior reconnection of the neural network impairing memory. The agonist prevented spatial memory impairment and LTP increase without effect of the drug per se. Taken together, all these results suggest a protective role of 7,8-DHF supporting the idea of a protective role of BDNF/TrkB pathway enhancement in PTSD and hence the value of 7,8-DHF as a putative treatment for PTSD patients.

Date of Award	8 Apr 2014
Original language	English
Awarding Institution	Universitat Autònoma de Barcelona (UAB)
Supervisor	Antonio Armario Garcia (Director) & César Venero (Director)