Microglia, the resident immune cells of the central nervous system (CNS), were traditionally believed to be set into action only in case of injury or disease. Accordingly, microglia were assumed to be inactive or resting in the healthy brain. However, recent studies revealed that microglia carry out active tissue sampling in the intact brain by extending and retracting their ramified processes while periodically contacting synapses. Microglial morphology and motility as well as the frequency and duration of physical contacts with synaptic elements were found to be modulated by neuronal activity, sensory experience and neurotransmission; however findings have not been straightforward. Microglial cells are the most morphologically plastic element of the CNS. This unique feature confers them the possibility to locally sense activity, and to respond adequately by establishing synaptic contacts to regulate synaptic inputs by the secretion of signaling molecules. Indeed, microglial cells can hold new roles as critical players in maintaining brain homeostasis and regulating synaptic number, maturation and plasticity. For this reason, a better characterization of microglial cells and cues mediating neuron-to-microglia communication under physiological conditions may help advance our understanding of the microglial behavior and its regulation in the healthy brain. This review highlights recent findings on the instructive role of neuronal activity on microglial motility and microglia-synapse interactions, focusing on the main transmitters involved in this communication and including newly described communication at the tripartite synapse.

INTRODUCTIONTau and neurodegeneration strongly correlate with cognitive impairment, as compared to amyloid. However, their contribution in explaining cognition and predicting cognitive decline in memory clinics remains unclarified.METHODSWe included 94 participants with Mini‐Mental State Examination (MMSE), tau positron emission tomography (PET), amyloidPET, fluorodeoxyglucose (FDG)PET, and MRI scans from Geneva Memory Center. Linear regression and mediation analyses tested the independent and combined association between biomarkers, cognitive performance, and decline. Linear mixed‐effects and Cox proportional hazards models assessed biomarkers’ prognostic values.RESULTSMetabolism had the strongest association with cognition (r = 0.712; p < 0.001), followed by tau (r = ‐0.682; p < 0.001). Neocortical tau showed the strongest association with cognitive decline (r = ‐0.677; p < 0.001). Metabolism mediated the association between tau and cognition and marginally mediated the one with decline. Tau positivity represented the strongest risk factor for decline (hazard ratio = 32).DISCUSSIONTau and neurodegeneration synergistically contribute to global cognitive impairment while tau drives decline. The tauPET superior prognostic value supports its implementation in memory clinics.HIGHLIGHTS Hypometabolism has the strongest association with concurrent cognitive impairment. Neocortical tau pathology is the main determinant of cognitive decline over time. FDG‐PET has a superior value compared to MRI as a measure of neurodegeneration. The prognostic value of tau‐PET exceeded all other neuroimaging modalities.