Microglia express functionally heterogeneous AMPA (α-amino-hydroxy-5-methyl-isoxazole-4-propionate)-type of receptors (Noda et al. 2000; Hagino et al. 2004) and contribute to glutamate (Glu)-mediated neuron-glia interaction (Bezzi et al. 2001) . Microglia express highly Ca²⁺ impermeable AMPA receptors due to the expression of GluA2 subunit . In addition, expression of plasmalemmal GluA2 subunits significantly increases upon activation of microglia, for example after treatment by lipopolysaccharide (LPS) (Beppu et al. 2013) . Since a decreased expression of GluA2 was reported in some of the neurodegenerative diseases such as AD and Creutzfeldt-Jakob disease (Ferrer and Puig 2003; Carter et al. 2004), functional change in GluA2-deficient microglia was investigated, showing higher Ca²⁺-permeability, consequently inducing significant increase in the release of pro-inflammatory cytokine, such as tumor necrosis factor-α (TNF-α). GluA2-deficient mouse brain also showed more neurotoxicity in response to kainic acid (Beppu et al. 2013) . Therefore, involvement of microglia in glutamatergic synaptic transmission may be also important to understand the mechanism of some neurodegeneration in which low GluA2 is suggested (Noda and Beppu 2013) .

In the hypothalamus and neurohypophysis of rats with streptozotocin (STZ)-induced diabetes, the expression of GluA2/3 was progressively down-regulated, being hardly detected at 4 months of STZ-diabetes, together with up-regulation of N-methyl D-aspartate receptor (NMDAR) subunit GluN1 and neuronal nitric oxide synthase (nNOS). In addition, both astrocytes and microglia appeared activated. Therefore, it was speculated that the glutamate receptors and NO are linked to overactivation of paraventricular and supraoptic nuclei leading ultimately to cell death (Luo et al. 2002) . The lack of GluA2/3 in microglia may also contribute to the cell death .

Microglia express kainate (KA) receptor subunits (Yamada et al. 2006; Noda et al. 2000) and KA-induced current was affected by application of concanavalin A which is a positive modulator selective for KA-preferring receptors (subunits GluR5–GluR7 and KA-1 or KA-2) (Huettner 1990; Partin et al. 1993; Wong and Mayer 1993) , suggesting that only some of the KA-responsive cells express KA-preferring receptors and not only AMPA-preferring receptors (Noda et al. 2000). It was indicative of heterogeneous distribution of AMPA- and KA-preferring receptors among microglial cells; some cells express predominantly AMPA-preferring receptors, some cells express predominantly KA-preferring receptors, and some cells express both. The functional difference has not been identified yet .

Although NMDA-induced membrane currents were not observed in primary cultured microglial cells (Noda et al. 2000), it was reported that cortical microglia express NMDAR subunits in vitro and in vivo and activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain (Kaindl et al. 2012) . Microglia have unique NMDAR subunit expression with a high level of the GluN2D subunit that is distinct from that found in neurons, indicating distinct NMDAR subunit assembly. The pathophysiologic relevance of microglial NMDARs is particularly high, as they confer sensitivity to excitotoxic cortical injury that is likely to be significant for a large variety of neurological diseases . For example, after stroke , glutamate released by damaged neurons in the infarct core can diffuse to nearby cells, and this can lead to an activation of microglia via their NMDARs and render them neurotoxic. Conversely, loss of function of the microglial NMDARs protects from gray matter damage .

Microglial cells also bear metabotropic glutamate receptors (mGluRs) (Biber et al. 1999; Farso et al. 2009; Taylor et al. 2002) ; mGluR1,5 (Group I) is linked to intracellular Ca²⁺ signaling, while mGluR2,3 (Group II) (Taylor et al. 2002) and mGluR4,6,8 (Group III) (Taylor et al. 2003) are coupled to adenosine 3′:5′ cyclic monophosphate (cAMP) and involved in regulation of TNF-α release and microglial cytotoxicity (Taylor et al. 2005). Since mGluRs is proposed as targets for multipotential treatment of neurological disorders (Byrnes et al. 2009) , microglial mGluRs may be critical regulators in neuron to glia transmissions especially under pathological state .

The main type of ionotropic purinoceptors expressed in mature microglial cells areP2X₄ and P2X₇ receptors. The P2X₄ receptors are also constitutively expressed in microglia and contribute to microglial activation in particular in the context of neuropathic pain . Increased levels of P2X₄ receptors was found in activated microglia (Tsuda et al. 2003) , whereas intrathecal injection of cultured microglia bearing P2X₄ receptors induced allodynia in the absence of peripheral nerve damage (Inoue and Tsuda 2009) . Involvement of P2X₄ in KA-induced status epilepticus was also reported (Ulmann et al. 2013) .

The P2X₇ receptors are involved in various neuropathologies (Franke et al. 2012) and contribute to various aspects of microglial reactions. P2X₇ receptors are abundantly present in immune cells and mediate many immune reactions, including the processing and the release of various cytokines . Microglial cells constitutively express P2X₇ receptors and various brain lesions and neuropathologies (such as, for example, MS, ALS and AD) induce substantial up-regulation of P2X₇ receptors expression (Sperlagh et al. 2006; Verkhratsky et al. 2009a) . Activation of P2X₇ receptors regulates multiple microglial processes from microglial activation to apoptotic death. Stimulation of P2X₇ receptors was reported to be necessary for microglial activation by amyloid-β (Aβ) protein (Sanz et al. 2009) , and P2X₇ receptors control microglial secretion of pro-inflammatory factors (see (Kettenmann et al. 2011) and references therein). Incidentally, over-expression of P2X₇ receptors in microglia triggers their activation in the in vitro system in complete absence of any other exogenous factors (Monif et al. 2009) . Recently P2X₇ receptor was reported to regulate microglial survival in living brain tissues (Eyo et al. 2013) . Removal of extracellular Ca²⁺ or application of a potent P2X₇ receptor antagonist, protected microglial cell death. These pharmacological results were complemented by studies in tissue slices from P2X₇ receptor null mice, in which oxygen-glucose deprivation (OGD)-induced microglial cell death was reduced by nearly half. These results indicate that stroke-like conditions induce Ca²⁺-dependent microglial cell death that is mediated in part by P2X₇ receptor. Increased neocortical expression of the P2X₇ receptor after status epilepticus and anticonvulsant effect of P2X₇ receptor antagonist were also reported (Jimenez-Pacheco et al. 2013) . From a therapeutic standpoint, these findings could help direct novel approaches to enhance microglial survival and function following stroke and other neuropathological conditions .

Microglia express several metabotropic purinoceptors with predominant appearance of P2Y₂, P2Y₆, P2Y₁₂, and P2Y₁₃ receptors. Stimulation of these receptors as a rule triggers Ca²⁺ signals that often involve endoplasmic reticulum Ca²⁺release and store-operated Ca²⁺ influx; overstimulation of P2Y pathways can produce a long-lasting activation of the latter that can contribute to various aspects of microglial activation (Toescu et al. 1998) . The P2Y₆ receptors, distinctively sensitive to UDP, regulate microglial phagocytosis (Koizumi et al. 2007) , whereas ADP-preferring P2Y₁₂ receptors are fundamental for acute microglial responses to pathological insults, for morphological activation, membrane ruffling and chemotaxis (Verkhratsky et al. 2009a) . In addition P2Y₁₂ receptors are linked to integrin-β1 signaling, which regulates extension of microglial processes (Ohsawa et al. 2010; Eyo and Wu 2013) . In the spinal cord P2Y₁₂ receptors are involved in the genesis of neuropathic pain (Inoue and Tsuda 2009) .

As mentioned above, neuron-to-microglia purinergic signaling regulates microglial extension and retraction (see review (Eyo and Wu 2013)). In the event of neuronal injury, neurons release purines including ATP which can be degraded by endogenous enzymes into ADP and adenosine. Released purines diffuse in the extracellular space and activate P1 adenosine (A₃) and P2Y (P2Y₁₂) receptors on microglia that act in concert.

Recently, it was shown that soluble Aβ peptide 1–42 induced self-uptake in microglia through pinocytosis, a process involving activation of P2Y₄ receptors by autocrine ATP signaling. It demonstrates a previously unknown function of ATP as a “drink me” signal for microglia and P2Y₄ receptors as a potential therapeutic target for the treatment of AD (Li et al. 2013) .

Adenosine receptors of P1 type are represented by classical seven-transmembrane spanning G protein-coupled receptors and are subclassified into adenosine A1, A2_A, A2_B, and A3 receptors with distinct pharmacological and functional properties. All four types of adenosine receptors were identified at the mRNA level in cultured rat microglia (Fiebich et al. 1996b) . As mentioned above, purinergic activation leads to extension of microglial processes towards the injury site. Following microglial activation , adenosine can also activate A2_A receptors that mediate microglial branch retraction. First, a role for the adenosine A2_A receptor in microglial cytoskeletal rearrangements was suggested (Orr et al. 2009) . Adenosine A_2B receptors mediate an increase in interleukin (IL)-6 in human astroglioma cells (Fiebich et al. 1996a) . Recently, there was a report that microglia also express A₁ receptor which is up-regulated upon ATP treatment. Moreover, selective stimulation of A₁ receptors inhibits morphological activation of microglia, possibly by suppressing the Ca²⁺ influx induced by ATP. Microglial cells, pretreated with the A₁ receptor agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone (Luongo et al. 2014) .