ASTRO_ECM · Deciphering the role of astrocytes in chronic depression.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2018-05-01 → 2020-04-30
- EU contribution
- €159,461
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Deciphering the role of astrocytes in chronic depression.
Depression is one of the most detrimental psychiatric disorders, accounting for severe disease burden and increased risk of mortality. According to the World Health Organization (WHO), each year, 25% of Europe’s population experiences depression or anxiety, resulting in immense societal costs and substantial decline in quality of life of patients and their families. Despite coordinated efforts from researchers and clinicians alike, the underlying cause of depression remains unknown, rendering available therapies inadequate for 3 out of 4 people suffering from the disorder. During the past decades, the study of communication between neuronal cells and its disruption in depression has been in the spotlight. Although this has led to a deeper understanding of the disease mechanisms, scientific and therapeutic breakthroughs are sparse. In order to move the field further, there is an imperative need to shift focus towards other, often overlooked, mediators of the depressive state. To this end, this proposal aimed to identify functional contributions of a unique brain cell population, the astrocytes, to chronic depression. Astrocytes facilitate information relay in the brain by shaping synaptic connectivity and functional dynamics, and are thus, considered fundamental units of plasticity in the central nervous system. Clinical and preclinical data support morphological changes of astrocytes in depression, as well as alterations in their molecular composition. However, the functional significance of these changes is largely unknown, and the molecular mechanisms underlying them are yet to be identified. A tangible target for astrocyte-mediated effects in depression is the extracellular matrix (ECM), a network of molecules that are indispensable for synaptic and structural plasticity in the brain. Astrocytes are responsible for the synthesis and release of ECM, which, by itself, has been implicated in depressive symptoms and antidepressant response. Together, astrocytes and astrocyte-derived ECM form a possible, and at present, unexplored, substrate for the pathophysiology of depression. This proposal aimed to decipher the role of astrocytic dysfunction in chronic depression and to establish astrocyte-derived ECM as a novel target for potent antidepressant effects. Initial conclusions of the action support a role for astrocyte dysfunction in depression-like cognitive decline, a robust modulation of ECM in the transition from acute stress to chronic depression, and consistent antidepressant effects of (pharmacological or genetic) ECM manipulation in preclinical models of depression. Together, these initial results lay solid foundations for future studies addressing the contribution of astrocytes and the ECM in depression and antidepressant treatment.
Data: CORDIS, © European Union
Project objective
Depression is a debilitating psychiatric disorder that affects 1 in 7 people worldwide. Despite coordinated efforts from researchers and clinicians alike, the neurobiological substrates of depression remain largely unknown. As a result, therapeutic options against depression are inadequate.Using a valid preclinical model, I recently demonstrated that depression alters the molecular composition of astrocytes and the organization of extracellular matrix (ECM), an assembly of molecules that are primarily synthesized and released by astrocytes. This results in disrupted information relay in the hippocampus and in cognitive impairment, both commonly seen in depressed patients. Thus, my work suggests a role of astrocytic (dys)function in the depressive state. In the proposed project, I aim to unravel the contribution of astrocytes in the pathophysiology of depression. First, I will address how the depressive state affects astrocyte proteome, morphology and function. Second, I will address the role of astrocytes and astrocyte-derived ECM in the manifestation of depression at the molecular, cellular and the behavioural level. To reach my goals, I will make use of genetically engineered mice that allow for visualization, metabolic labeling and targeting of astrocytes. These mice will be subjected to social defeat to induce a chronic depressive state. I will study astrocyte morphology, physiology and proteome alterations in depressed mice vs. controls. After establishing astrocyte-specific changes, I will employ i) viral vector-assisted silencing of the expression of astrocytic genes contributing to the ECM and ii) designer receptor exclusively activated by designer drugs (DREADDs)-assisted modulation of astrocyte activity. I will then assess whether these interventions can ameliorate the depressive state. With this integrative approach I aim to uncover novel molecular pathways mediating the depressive state and to identify new targets for the treatment of depression.
Original text from CORDIS.
Participants
- DEUTSCHES ZENTRUM FUR NEURODEGENERATIVE ERKRANKUNGEN EV · BonnCoordinatorGermany
Links
Data: CORDIS, © European Union