Novel microglial calcium signal is a rapid sensor of neuronal damage in vivo

In the healthy adult brain microglia, the main im­mune-com­pe­tent cells of the CNS, have a dis­tinct (so-called “rest­ing”, see image) phe­notype. Rest­ing microglia can only be stud­ied in vivo since any isolation of brain tissue inevitably trig­gers microglial activation. Us­ing in vivo two-photon imag­ing we obtained a first di­rect in­sight into Ca²⁺ signaling in rest­ing cortical microglia.

 

We have found that the majority of microglial cells show no spontaneous Ca²⁺ transients at rest and in conditions of strong neuronal activity. However, they reliably respond with large, generalized Ca²⁺ transients to damage of an individual neuron. These damage-induced Ca²⁺ transients (DICTs) have a short latency (0.4-4 s) and occur only in microglial cells localized to the immediate vicinity of the damaged neuron (< 50 µm cell body-to-cell body distance). DICTs are occluded by the agonists of metabotropic P2Y receptors and require Ca²⁺ release from the intracellular Ca²⁺ stores.

The functional role of these long-lasting, generalized microglial Ca²⁺ signals remains to be explored. DICTs occur immediately after neuronal damage (on the millisecond-to-second scale) and thus long before the damage-induced changes in microglial morphology (initiated within the first few minutes) take place. Therefore DICTs most likely operate as a switch, triggering processes relevant to microglial activation. Such processes may include (i) reorganization of actin cytoskeleton, (ii) CREB phosphorylation, (iii) gene expression and de novo protein synthesis (e.g. production of cytokines and chemokines, cyclooxygenase-2 and BDNF), (iv) release of pro- and/or anti-inflammatory mediators and (v) microglial phagocytosis. The fact that DICTs remain restricted in space suggests that single-cell damage is treated as a local event, involving only immediately adjacent microglia.

Taken together our data suggest that in vivo somatic Ca²⁺ signaling in microglia is not involved in the surveillance of the extracellular milieu or in the detection of physiological levels of neuronal/astroglial activity. Rather, it functions as highly sensitive and specific signal for recognition of the damage in the microglial microenvironment.