Microglia-neuron interactions play a crucial role in several neurological disorders characterized by altered neural network excitability, such as epilepsy and neuropathic pain. While a series of potential messengers have been postulated as substrates of the communication between microglia and neurons, including cytokines, purines, prostaglandins, and nitric oxide, the specific links between messengers, microglia, neuronal networks, and diseases have remained elusive. Brain-derived neurotrophic factor (BDNF) released by microglia emerges as an exception in this riddle. Here, we review the current knowledge on the role played by microglial BDNF in controlling neuronal excitability by causing disinhibition. The efforts made by different laboratories during the last decade have collectively provided a robust mechanistic paradigm which elucidates the mechanisms involved in the synthesis and release of BDNF from microglia, the downstream TrkB-mediated signals in neurons, and the biophysical mechanism by which disinhibition occurs, via the downregulation of the K+-Cl？ cotransporter KCC2, dysrupting Cl？homeostasis, and hence the strength of - and glycine receptor-mediated inhibition. The resulting altered network activity appears to explain several features of the associated pathologies. Targeting the molecular players involved in this canonical signaling pathway may lead to novel therapeutic approach for ameliorating a wide array of neural dysfunctions. 1. Introduction Once simply considered as the “guardians” of the central nervous system (CNS), microglia have more recently emerged as key players in regulating neuronal network excitability. Indeed, physical and chemical alterations in the extracellular environment promote the synthesis and release of several microglia-derived molecules which, in turn, shape neuronal circuit function. The effects of such microglia-neuron interactions were found to be critical in the course of different central disorders, and in particular seminal studies provided significant evidence for a role of microglia in the pathogenesis of seizures (for review see [1, 2]) which was associated with increased glutamatergic transmission through the potentiation of NMDA receptor-mediated activity [3]. However, from a theoretical point of view, raising network excitability can be equally achieved through increasing excitatory inputs or removing inhibitory ones. In fact, unmasking silent interconnections can be better achieved through disinhibition than enhanced excitation. Furthermore, disinhibition has been shown as an upstream substrate of
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