Calcium dynamics in astrocytes represent a fundamental signal that through gliotransmitter release regulates synaptic plasticity and behaviour. Here we present a longitudinal study in the PS2APP mouse model of Alzheimer’s disease (AD) linking astrocyte Ca²⁺ hypoactivity to memory loss. At the onset of plaque deposition, somatosensory cortical astrocytes of AD female mice exhibit a drastic reduction of Ca²⁺ signaling, closely associated with decreased endoplasmic reticulum Ca²⁺ concentration and reduced expression of the Ca²⁺ sensor STIM1. In parallel, astrocyte-dependent long-term synaptic plasticity declines in the somatosensory circuitry, anticipating specific tactile memory loss. Notably, we show that both astrocyte Ca²⁺ signaling and long-term synaptic plasticity are fully recovered by selective STIM1 overexpression in astrocytes. Our data unveil astrocyte Ca²⁺ hypoactivity in neocortical astrocytes as a functional hallmark of early AD stages and indicate astrocytic STIM1 as a target to rescue memory deficits.

The human brain is composed of nearly one hundred billion neurons and an equal number of glial cells, including macroglia, i.e., astrocytes and oligodendrocytes, and microglia, the resident immune cells of the brain. In the last few decades, compelling evidence has revealed that glial cells are far more active and complex than previously thought. In particular, astrocytes, the most abundant glial cell population, not only take part in brain development, metabolism, and defense against pathogens and insults, but they also affect sensory, motor, and cognitive functions by constantly modulating synaptic activity. Not surprisingly, astrocytes are actively involved in neurodegenerative diseases (NDs) and other neurological disorders like brain tumors, in which they rapidly become reactive and mediate neuroinflammation. Reactive astrocytes acquire or lose specific functions that differently modulate disease progression and symptoms, including cognitive impairments. Astrocytes express several types of ion channels, including K⁺, Na⁺, and Ca²⁺ channels, transient receptor potential channels (TRP), aquaporins, mechanoreceptors, and anion channels, whose properties and functions are only partially understood, particularly in small processes that contact synapses. In addition, astrocytes express ionotropic receptors for several neurotransmitters. Here, we provide an extensive and up-to-date review of the roles of ion channels and ionotropic receptors in astrocyte physiology and pathology. As examples of two different brain pathologies, we focus on Alzheimer’s disease (AD), one of the most diffuse neurodegenerative disorders, and glioblastoma (GBM), the most common brain tumor. Understanding how ion channels and ionotropic receptors in astrocytes participate in NDs and tumors is necessary for developing new therapeutic tools for these increasingly common neurological conditions.

The purinergic P2X7 receptor (P2X7R) is a unique ATP-gated ion channel that requires unusually high concentrations of extracellular ATP (eATP) for activation, making it a sensor of cellular stress and injury in the central nervous system. This review provides a comprehensive overview of P2X7R expression and function in glial cells, with a particular focus on microglia and astrocytes. We first outline the molecular characteristics of P2X7R and its distribution in brain cell types. In microglia, P2X7R regulates a broad spectrum of processes, including phagocytosis, autophagy, proliferation, and ultimately cell death, underscoring its dual role in neuroprotection and neurotoxicity. In astrocytes, P2X7R contributes to gliotransmission and inflammatory signaling, influencing neuronal excitability and synaptic function. We further explore the role of P2X7R in the context of both Alzheimer’s disease and epilepsy, where a dysregulated eATP-P2X7R signaling axis exacerbates neuroinflammation and glial dysfunction. Understanding the cell-specific roles of P2X7R in physiology and pathology provides new insights into glial biology and highlights its potential as a therapeutic target in brain diseases.

Alzheimer’s disease (AD) is a hereditary and sporadic neurodegenerative illness defined by the gradual and cumulative loss of neurons in specific brain areas. The processes that cause AD are still under investigation and there are no available therapies to halt it. Current progress puts at the forefront the “calcium (Ca²⁺) hypothesis” as a key AD pathogenic pathway, impacting neuronal, astrocyte and microglial function. In this review, we focused on mitochondrial Ca²⁺ alterations in AD, their causes and bioenergetic consequences in neuronal and glial cells, summarizing the possible mechanisms linking detrimental mitochondrial Ca²⁺ signals to neuronal death in different experimental AD models.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca²⁺-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca²⁺ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca²⁺ indicators, allowing the direct assessment of Ca²⁺ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca²⁺-ATPase and lower ER resting Ca²⁺ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.