An astrocytic specific pathway has been identified to be used in a method and pharmaceutical compositions for treating major depression and chronic-stress related disorders. It has been successfully tested in preventing depressive-like behavior in rodents and it is expected to be applicable in humans after further proof-of-concept.
Astrocytes display unique properties that allow them to influence network signaling and consequently modulate behavior responses, and are proposed as methods to prevent depression through pharmacology.
The present disclosure provides novel molecular, functional and mechanistic data on the relevance of astrocytic FoxO1 pathway in the development of depressive-like behavior in an animal model of major depression. Herein it is shown that blocking astrocyte intracellular calcium (which silences calcium-dependent signaling) causes a surprising resilience to the installation of the depressive phenotype in the depression model. Astrocytes process excitatory input through complex intracellular calcium elevations, that drive intrinsic astrocyte activity and responses to surrounding neurons. By taking advantage of a mouse model, the homeostatic house-keeping functions are preserved while silencing the astrocyte activity dependent on excitatory inputs. The exposure of this model to chronic mild stress revealed a surprising resilience to the expected depressive phenotype. Specifically, this resilience consisted of more self-care, less weight loss, less learned helplessness, similarly to their non-stressed counterparts.
The overexpression in astrocytes of the hippocampus, one key region in the pathophysiology of depression, led to the prevention of installation of depressive-like behavior, resulting in motivation levels expressed in self-care behavior like controls in the animal model of depression.
Innovative Aspects and Main advantages
The prevalence of depressive disorders is dramatically increasing, affecting more than 280 million people worldwide. The pathophysiology of depression is still poorly understood which justifies the lack of highly effective treatments, leading to a failure of complete remission in 65% of the patients. Depressive behavior was classically characterized by neuronal impairments in cortico-limbic networks, however the role of astrocytes, a ubiquitous glial cell type in the brain, has been overlooked and merely regarded as supporting neuronal function.
The obtained results show for the first time that the astrocytic pathway is involved in the resilience to chronic stress, of great value to be used in the prevention or treatment of symptoms of depression.
Stage of Development
The method has been successfully tested in rodents.
Intellectual Property Rights
A provisional patent application was submitted in 2022.
The team is looking for companies willing to discuss research collaborations.