Microglial control of synaptic function in stress response and vulnerability to depression



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 and integrated approach that combines studies conducted in animal models, in post-mortem brain samples from depressed individuals, and a clinical trial. Our analyses will range from cellular and subcellular neuroimaging, high-throughput molecular biology, state-of-the-art microglia-based transcriptomics, proteomics and metabolomics, to classical electrophysiology, and behavioral phenotyping. By focusing on microglia-synapse interactions, our project will provide novel insights into the molecular cellular and 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.

Allmän beskrivning

Major depressive disorder (MDD) is one of the most relevant public health challenges at the clinical, social and economic levels, costing over 120 billion euros in Europe alone. Alteration in the synapses, which are the structures responsible for communication among the principal brain cells, i.e. the neurons, has been hypothesized to underlie the onset of MDD. However, the mechanisms through which synaptic dysfunction contributes to this psychopathology are only scarcely known. Microglia, which are immune cells of the brain, play a key role in regulating synaptic function and neuronal activities in the healthy and diseased brain. We therefore hypothesize that microglia are critically involved in the brain changes underlying both the onset of and the remission from MDD. Consequently, treatments able to modulate microglial function hold the promise of providing novel and more effective therapeutic strategies to treat this psychopathology. The MicroSynDep consortium aims at exploring such hypothesis. To this goal, the consortium brings together a multidisciplinary partnership of European- and Canadian-leading experts, including clinicians and basic scientists, and will combine, in a translational perspective that is from preclinical work to clinical applications, studies on human brain and depressed patients with basic neurobiolgical research in animal models. We will employ a wide range of cutting-edge technologies to unravel the impairment of microglia-synapse interaction in MDD. Ultimately, the MicroSynDep project will lead to develop and implement in the clinics innovative treatment options for depression.
Kort titelMicroglial control of synaptic function
Gällande start-/slutdatum01/10/201831/12/2021


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