Astrocyte Ca(2+) signalling has been proposed to link neuronal information in different spatial-temporal dimensions to achieve a higher level of brain integration. However, some discrepancies in the results of recent studies challenge this view and highlight key insufficiencies in our current understanding. In parallel, new experimental approaches that enable the study of astrocyte physiology at higher spatial-temporal resolution in intact brain preparations are beginning to reveal an unexpected level of compartmentalization and sophistication in astrocytic Ca(2+) dynamics. This newly revealed complexity needs to be attentively considered in order to understand how astrocytes may contribute to brain information processing.

Glial calcium dynamics in space and time: Astrocytes use calcium signals to process information received from neighboring brain cells and thus generate modulatory responses at the local or network level. Previous studies have relied on calcium imaging in line scans or in a single focal plane mostly focusing on the cell bodies of astrocytes. Bindocci et al. used more powerful scanners that can rapidly scan many focal planes. They combined this technique with advanced genetic tools for monitoring calcium gradients with high sensitivity, which allowed three-dimensional calcium imaging of a whole astrocyte. Most of the basal calcium activity occurred in the astrocyte processes, some in the endfeet, and only a small fraction actually in the cell bodies of astrocytes. Science , this issue p. eaai8185

Low-threshold (T-type) Ca ²⁺ channels encoded by the Ca _V 3 genes endow neurons with oscillatory properties that underlie slow waves characteristic of the non-rapid eye movement (NREM) sleep EEG. Three Ca _V 3 channel subtypes are expressed in the thalamocortical (TC) system, but their respective roles for the sleep EEG are unclear. Ca _V 3.3 protein is expressed abundantly in the nucleus reticularis thalami (nRt), an essential oscillatory burst generator. We report the characterization of a transgenic Ca _V 3.3 ^{− / −} mouse line and demonstrate that Ca _V 3.3 channels are indispensable for nRt function and for sleep spindles, a hallmark of natural sleep. The absence of Ca _V 3.3 channels prevented oscillatory bursting in the low-frequency (4–10 Hz) range in nRt cells but spared tonic discharge. In contrast, adjacent TC neurons expressing Ca _V 3.1 channels retained low-threshold bursts. Nevertheless, the generation of synchronized thalamic network oscillations underlying sleep-spindle waves was weakened markedly because of the reduced inhibition of TC neurons via nRt cells. T currents in Ca _V 3.3 ^{− / −} mice were <30% compared with those in WT mice, and the remaining current, carried by Ca _V 3.2 channels, generated dendritic [Ca ²⁺ ] _i signals insufficient to provoke oscillatory bursting that arises from interplay with Ca ²⁺ -dependent small conductance-type 2 K ⁺ channels. Finally, naturally sleeping Ca _V 3.3 ^{− / −} mice showed a selective reduction in the power density of the σ frequency band (10–12 Hz) at transitions from NREM to REM sleep, with other EEG waves remaining unaltered. Together, these data identify a central role for Ca _V 3.3 channels in the rhythmogenic properties of the sleep-spindle generator and provide a molecular target to elucidate the roles of sleep spindles for brain function and development.

In chronic inflammatory diseases of the central nervous system (CNS), immune cells persisting behind the blood-brain barrier are supposed to promulgate local tissue destruction. The drivers of such compartmentalized inflammation remain unclear, but tissue-resident memory T cells (T _RM ) represent a potentially important cellular player in this process. Here, we investigated whether resting CD8 ⁺ T _RM persisting after cleared infection with attenuated lymphocytic choriomeningitis virus (LCMV) can initiate immune responses directed against cognate self-antigen in the CNS. We demonstrated that time-delayed conditional expression of the LCMV glycoprotein as neo-self-antigen by glia cells reactivated CD8 ⁺ T _RM . Subsequently, CD8 ⁺ T _RM expanded and initiated CNS inflammation and immunopathology in an organ-autonomous manner independently of circulating CD8 ⁺ T cells. However, in the absence of CD4 ⁺ T cells, TCF-1 ⁺ CD8 ⁺ T _RM failed to expand and differentiate into terminal effectors. Similarly, in human demyelinating CNS autoimmune lesions, we found CD8 ⁺ T cells expressing TCF-1 that predominantly exhibited a T _RM -like phenotype. Together, our study provides evidence for CD8 ⁺ T _RM -driven CNS immunopathology and sheds light on why inflammatory processes may evade current immunomodulatory treatments in chronic autoimmune CNS conditions.