JCB_201607048 2979..2990

Microglial cells are immune components of the brain, and their activation has been established as a hallmark of brain pathologies (Ransohoff and Cardona, 2010). However, microglia are also partners of neuronal functions in the healthy brain (Tremblay et al., 2011). In particular, they are implicated in the rapid modulation of excitatory synapses, and microglial stimulations induce specific responses of excitatory neurotransmission (Béchade et al., 2013). For instance, fractalkine activates the microglia-specific CX3CR1 and induces a transient reduction of the amplitude of evoked excitatory postsynaptic currents (PSCs) in CA1 pyramidal neurons (Ragozzino et al., 2006; Clark et al., 2015). Similarly, lipopolysaccharide (LPS), which specifically activates the microglial Toll-like receptor 4, triggers an astrocyte-mediated increase in the frequency of AMPAergic evoked excitatory PSCs (Pascual et al., 2012). Finally, video microscopic analysis of microglia–synapse structural relationships has demonstrated that microglia respond to neuronal activity by modulating the physical contacts between their processes and the excitatory synaptic elements (Wake et al., 2009; Tremblay et al., 2010; Li et al., 2012). Interactions between microglia and inhibitory synapses have mostly been studied as long-term regulations occurring in pathologies. For instance, during peripheral nerve injury, spinal cord microglia produce brain-derived neurotrophic factor (BDNF), which induces a shift in chloride flux through GABAA receptors (GABAARs) in nociceptive neurons. This leads to an increase of their excitability and contributes to pain hypersensitivity (Coull et al., 2005). Furthermore, long-term activation of microglia may lead to physical deconnections between the preand postsynaptic elements of inhibitory synapses (Chen et al., 2014). In addition, immune-derived molecules such as major histocompatibility complex class I molecules (Oliveira et al., 2004) or prostaglandin E2 (PGE2), a major modulator of inflammatory pain (Harvey et al., 2004), regulate inhibitory synapses during diseases. However, microglia are not only actors of pathologies; they may also be involved in acute situations because they are highly dynamic cells that rapidly react to environmental modifications (Davalos et al., 2005; Nimmerjahn et al., 2005). Hence, microglia might also be involved in short-term regulation of inhibitory synapses. This hypothesis is supported by the fact that signaling molecules produced by microglia can rapidly modulate inhibitory synaptic function. For instance, TNF-α induces a rapid decrease of GABAergic synaptic strength associated with a down-regulation of cellsurface GABAAR (Pribiag and Stellwagen, 2013). Similarly, thrombospondin 1 (TSP1), which is also produced by microglia (Chamak et al., 1995), modulates the diffusion dynamic Microglia control excitatory synapses, but their role in inhibitory neurotransmission has been less well characterized. Herein, we show that microglia control the strength of glycinergic but not GABAergic synapses via modulation of the diffusion dynamics and synaptic trapping of glycine (GlyR) but not GABAA receptors. We further demonstrate that microglia regulate the activity-dependent plasticity of glycinergic synapses by tuning the GlyR diffusion trap. This microglia– synapse cross talk requires production of prostaglandin E2 by microglia, leading to the activation of neuronal EP2 receptors and cyclic adenosine monophosphate–dependent protein kinase. Thus, we now provide a link between microglial activation and synaptic dysfunctions, which are common early features of many brain diseases. Microglia control the glycinergic but not the GABAergic synapses via prostaglandin E2 in the spinal cord