Calcineurin Signalling in Astrocytes: From Pathology to Physiology and Control of Neuronal Functions

Calcineurin (CaN), a Ca²⁺/calmodulin-activated serine/threonine phosphatase, acts as a Ca²⁺-sensitive switch regulating cellular functions through protein dephosphorylation and activation of gene transcription. In astrocytes, the principal homeostatic cells in the CNS, over-activation of CaN is known to drive pathological transcriptional remodelling, associated with neuroinflammation in diseases such as Alzheimer's disease, epilepsy and brain trauma. Recent reports suggest that, in physiological conditions, the activity of CaN in astrocytes is transcription-independent and is required for maintenance of basal protein synthesis rate and activation of astrocytic Na⁺/K⁺ pump thereby contributing to neuronal functions such as neuronal excitability and memory formation. In this contribution we overview the role of Ca²⁺ and CaN signalling in astroglial pathophysiology focusing on the emerging physiological role of CaN in astrocytes. We propose a model for the context-dependent switch of CaN activity from the post-transcriptional regulation of cell proteostasis in healthy astrocytes to the CaN-dependent transcriptional activation in neuroinflammation-associated diseases.