Reciprocal Regulation between Resting Microglial Dynamics and Neuronal Activity In Vivo

Abstract

Microglia are the primary immune cells in the brain. Under physiological conditions, they typically stay in a "resting" state, with ramified processes continuously extending to and retracting from surrounding neural tissues. Whether and how such highly dynamic resting microglia functionally interact with surrounding neurons are still unclear. Using in vivo time-lapse imaging of both microglial morphology and neuronal activity in the optic tectum of larval zebrafish, we found that neuronal activity steers resting microglial processes and facilitates their contact with highly active neurons. This process requires the activation of pannexin-1 hemichannels on neurons. Reciprocally, such resting microglia-neuron contact reduces both spontaneous and visually evoked activities of contacted neurons. Our findings reveal an instructive role for neuronal activity in resting microglial motility and suggest the function for microglia in homeostatic regulation of neuronal activity in the healthy brain.

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Similar results were obtained when animals were reared in complete darkness during a critical period of visual cortex development (Tremblay et al, 2010). In contrast, increasing neuronal activity in zebrafish by either glutamate uncaging or repetitive visual stimulation results in increased contact by microglial processes, which preferentially ensheath neurons with high spontaneous calcium transients through a mechanism that likely involves calcium-induced release of ATP from neurons (Li et al, 2012b). Contact by microglial processes was also associated with a subsequent decrease in spontaneous spiking frequency (Li et al, 2012b).…”

“…In contrast, increasing neuronal activity in zebrafish by either glutamate uncaging or repetitive visual stimulation results in increased contact by microglial processes, which preferentially ensheath neurons with high spontaneous calcium transients through a mechanism that likely involves calcium-induced release of ATP from neurons (Li et al, 2012b). Contact by microglial processes was also associated with a subsequent decrease in spontaneous spiking frequency (Li et al, 2012b). Therefore, microglia appear to monitor synaptic function and alter their physiological behavior in response to changes in neuronal activity, which in turn can exert influence on the activity properties of contacted neurons.…”

Role of microglia in fungal infections of the central nervous system

“…18 Likewise, numerous studies have demonstrated microglia's own biological identity including the regulation of synaptic pruning and plasticity, [42][43][44] the spatial distribution of axonal projections, 45,46 and neuronal homeostasis and survival. 47,48 Alternatively, a current hypothesis proposes that microglial reactivity may be stimulated by damaged neurons with deficient signaling, the presence of circulatory plasma molecules in the CNS due to the BBB disruption, and peripheral leukocyte signaling mediated by cytokines after interactions with microbes or their antigens. 24 Major efforts in specifically dissecting the biology of microglia should focused on using epigenomics, comparative transcriptomics, proteomics, and other multidimensional technologies such as computational biology and 2-photon imaging.…”

A Role for Microglia in Repeated Stress-Induced Functional Changes in the Medial Prefrontal Cortex in Rodents

“…Since PGE 2 mediates the effect of repeated stress in attenuating mPFC dopaminergic activity [9], it is suggested that microglia regulate mPFC functions indirectly through PGE 2 and dopamine signaling. On the other hand, recent studies using in vivo brain imaging and electron microscopy, combined with mice deficient in microglial functions, have suggested a direct action of microglia on neurons for their functional and structural remodeling [15][16][17][18][19]. Since several groups including ours have reported that repeated stress induces microglial activation in various brain areas including the mPFC [9,11,[20][21][22], it is speculated that stressactivated microglia can directly affect functions of mPFC neurons.…”