Using brain-wide neuronal imaging at cellular resolution to discover principles of neuron activity modulation by microglia

• Applicant: Dr. Francesca Logiacco, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538928297

Microglia, the brain-resident immune cells, are highly dynamic in nature. In addition to their immune competence, has been shown that they play an unexpected role in neuronal activity modulation. Recent data from Prof. Schaefer laboratory and others revealed that microglia may sense changes in neighboring neuron activity and negatively feedback synaptic transmission, protecting the brain from excessive neuronal activation. This interneuron-like function places microglia at the heart of neuronal activity modulation. Prof. Schaefer laboratory showed that microglia depletion results in enhanced synchronized basal activity of striatal neurons and leads to increased neuronal responses to different neurostimulants, cumulating in a heightened seizure susceptibility in mice. An abnormal rise in neuronal firing has also been observed in visual cortex of microglia-deficient mouse brain or barrel cortex of mice with microglial Gi-signaling ablation. Consistent with previous findings 6, these studies place microglia in novel key roles of regulation of synaptic activity and prevention from aberrant neuronal activations. To investigate this novel microglial function in regulation of synaptic activity, I plan first to examine whether the microglia-driven negative feedback on neuronal activity and synaptic transmission is brain region-specific or does extend brain-wide to a large-scale network, during spontaneous mouse behavior. Second, I will inquire the effect of microglia on stimuli-induced neuronal activity for monitoring eventual diversities in microglia modulation of neuronal dynamics with respect to stimuli-correlated and -uncorrelated cortical areas. Once I identified the spatiotemporal range of microglia modulation of neuronal transmission in mouse neocortex, my following aim would be defining the mechanism that microglia apply to sense and negatively feedback synaptic activation. Prof. Schaefer laboratory found that microglia sense activity-dependent neuronal ATP release at the synapse and, by CD39 and CD73 ectonucleases, can rapidly metabolize ATP to adenosine, a potent neurosuppressant. Aiming to define how microglia modulate neuronal transmission, I propose first to examine microglia as source of the neurosuppressant adenosine. This study may further help to elucidate the expected contribution of microglia in the activity-dependent fluctuations of adenosine levels in the brain. The novel brain-wide imaging technique at cellular resolution, realized by Prof. Vaziri laboratory, will be used to record neuronal calcium events on live mice, before and after microglia depletion and, upon spontaneous and stimuli-induced behavior. To verify the adenosine-dependent modulation of neuronal synapses, these mice will be further crossed with CD39- and A1R- deficient mouse lines. This study has the potential to uncover the mechanisms by which microglia influence neuronal activity, adenosine dynamics, and associated brain functions.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Alipasha Vaziri, Ph.D.