Major depressive disorder (MDD) is one of the most relevant public health challenges at clinical, social and economic levels. One of the main causes of this burden is the limited comprehension of the molecular mechanisms underlying the pathology. Synaptic dysfunction, which has been suggested to be central to MDD, is determined by a complex interplay between different cell types, among which microglia exert a key role. In recent years, these cells were shown to be crucial for regulating synapses and remodeling of neuronal circuits. In the present project, we aim to study microglial implication in synaptic dysfunction in MDD and following exposure to chronic stress, the major risk factor for MDD. A further aim is to investigate the microglial role in the remission from MDD, which has been only limitedly explored. To these goals, we will exploit a multidisciplinary approach and our analyses will range from molecular, to electrophysiology, imaging and behavioral phenotyping. By focusing on microglia-synapse interactions, our project will provide novel insights into the molecular and cellular mechanisms underlying synaptic dysfunction in MDD and represent a point of major importance for the future development of novel therapeutic strategies that specifically target microglia, thus advancing the field of MDD treatment that has not substantially progressed over the last decades.
The present project is devoted to elucidating the role of microglia in mediating the effects of stress on synaptic dysfunction and, thus, in the vulnerability to MDD. In addition, in order to increase the originality and the innovative value of the project, it will investigate the role of microglia in restoring synaptic function and promoting remission from the psychopathology. The latter has been poorly investigated and its implementation is critical for the future development of innovative therapeutic strategies targeting microglia to treat MDD. In addition, we will work on both males and females because of the marked gender difference in the prevalence of MDD.Given the key role of the hippocampus in this pathology, we will focus on this brain area in the preclinical studies.
The project exploits a multidisciplinary approach and has a potential translational relevance. The added value of the collaboration lies in the complementary expertise of the research groups involved, in terms of technical and conceptual approaches, ranging from electrophysiological and molecular to behavioral and imaging phenotyping. Preclinical studies have been planned according to statistical considerations about power analysis to maximize the obtention of reliable results. In addition, the project is designed to minimize risks and enable collaboration across partners from the beginning; i.e. the research is truly integrated from conception and not just bringing together individual projects at the end. In addition, the different groups involved in the proposal already have ongoing collaborations, (i.e. Maggi, Tremblay and Branchi; Maggi and Fucile, Maggi and Catalano) and already produced results published in international scientific journal. At present, all partners possess the Ministerial authorization to use animal models indicated in the proposal. This will give them the possibility to conduct parallel experiments and to facilitate data and discussion exchanges.
By performing building a knowledge chain from molecular/cellular/electrophysiological and imaging techniques to the analysis of the behavior, the project will help in the identification of new promising leads for pharmacological treatment of MDD. They will also be a step of major importance for the future development of innovative cell therapies controlling the effector functions of microglia and their consequences on synaptic function.
References
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