Microglia modulate information processing in the mouse barrel cortex

Microglia, the main immune cells of the central nervous system, are crucial for maintaining brain homeostasis by modulating immune processes and neurovascular function. However, the mechanisms by which microglia regulate neuronal networks and local microcircuits remain incompletely understood. Here, we identify microglia as important modulators of neuronal network activity at the single-cell level and brain-wide functional connectivity in male mice. We show that in the absence of microglia or microglial P2Y12 receptor (P2Y12R), the baseline firing rate of putative interneurons was increased, while whisker-stimulation-induced sensory responses remained unchanged in microglia-depleted and P2Y12R KO animals . Increase in cortical delta oscillations in both models and increased single neuron phase coupling to delta-band rhythms in microglia-depleted mice revealed cortical hypersynchrony. Microglia depletion led to a significant reduction in connectivity between the contralateral barrel cortex and the anatomically connected ventral posteromedial nucleus of the thalamus (VPMb) during somatosensory stimulation, while resting-state functional connectivity remained unchanged. Similarly, genetic blockade of P2Y12R resulted in diminished functional connectivity within this thalamocortical network. Our findings suggest that cortical interneuron hyperexcitability due to dysfunction of microglia could be a key cause for local hypersynchrony relevant to sensory processing. Significance statement Microglia have been shown to modulate neuronal activity, but the underlying mechanisms are insufficiently defined. In particular, it is not well understood how microglia could shape excitatory / inhibitory balance in the cerebral cortex and whether such modulatory processes could alter sensory processing. Here, we studied single cell-level effects in the barrel cortex by using two established models of microglia dysfunction. We show that the absence of microglia or the purinergic microglial receptor, P2Y12R, have both large-scale effects on thalamocortical networks and cortical slow oscillations, while specifically shape the firing rate of interneurons in cortical microcircuits. Such neuroglial interactions could have broad impact on sensory processing in health and under different disease states.