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Deciphering the role of astrocytes in chronic depression.

Periodic Reporting for period 1 - ASTRO_ECM (Deciphering the role of astrocytes in chronic depression.)

Reporting period: 2018-05-01 to 2020-04-30

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.
The main objective of the project was to uncover the contribution of astrocytes and astrocyte-derived extracellular matrix (ECM) in the pathophysiology of depression, and in antidepressant response.
During the first year of the action, initial experiments revealed the necessity of astrocyte signalling for intact memory function, a higher cognitive process that is severely affected by depression. These experiments documented how astrocyte dysfunction potentially underlies cognitive decline in depression, and informed future research directions to directly test this hypothesis. Similarly, several novel techniques were applied to examine the morphological and electrophysiological characteristics of astrocytes during chronic depression. These initial studies will help determine the critical changes in astrocyte physiology and activity that might precede the establishment of the depressive state.
Furthermore, a series of experiments described how stress, a main contributor to depression onset, affects the organization of the ECM in the short- and in the long-term. This uncovered a dynamic ECM regulation in the days, weeks and months after severe stress exposure, leading up to depression. Profiling the developmental trajectory of stress-induced ECM regulation allowed for targeted pharmacological or genetic interventions, aimed to ameliorate the effects of stress and eventually, prevent the establishment of chronic depression. Preliminary results showed the antidepressant potential of a novel ECM-targeting compound early after stress, and uncovered a lasting antidepressant effect of genetic ECM manipulation. Together, these two strategies can help shape novel therapeutic avenues for depression in humans.
Due to its significant scientific and potential societal impact, the combined body of work performed in the first year of the action was disseminated in several occasions, including (oral or poster) presentations in: two international conferences, one advanced workshop and three seminars in research institutes.
Thus far, the project has been successful in addressing the role of extracellular matrix (ECM) in chronic depression, while laying the foundation for future studies on the involvement of astrocytes and, in particular, astrocyte-derived ECM in the pathophysiology and treatment of this debilitating disease. Two manuscripts in preparation (one original research and one review article) and at least one additional original research publication resulting from the action, will contribute significantly to our understanding of the molecular underpinnings of depression and antidepressant response.
In addition to direct contribution to scientific knowledge, the action resulted in the strengthening of the relationships between two international research groups that share unique but complimentary expertise. As the two groups actively pursue collaborations, such as joint funding applications, personnel training and open material exchange, this creates exceptional ground for significant scientific advancements in the study of psychiatric disorders.
Importantly, the project attracted an industry partner, with expertise on drug discovery. As a result, novel compounds with antidepressant potential were directly utilized, making a tangible impact in respect to novel therapeutic targets for depression.
Taken together, and due to the action's nature, a double future contribution to societal equilibrium and health is envisioned. First, by identifying basic neurobiological mechanisms of depression, this action could uncover potential vulnerability factors, eventually facilitating disease prevention. Second, by putting forth original treatment directions, this project could assist in designing novel, effective interventions for depression, with minimal side effects. Although still at the preclinical level, with a long way to the clinic, this can have a huge impact for the 50% of depressed individuals that remain untreated, and the accompanied estimated €170 billion annual costs of mood disorders and anxiety in the EU.