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.
